The Synthesis of 5-Amino-dihydrobenzo[b]oxepines and 5-Amino-dihydrobenzo[b]azepines via Ichikawa Rearrangement and Ring-Closing Metathesis

Article abstract of DOI:10.1021/acs.joc.6b01691

The combination of Ichikawa's rearrangement and a ring-closing metathesis reaction of allyl carbamates is presented as a method for the preparation of 5-amino-substituted 2,5-dihydro-benzo[b]oxepines, 2,5-dihydro-benzo[b]azepines, and 2,5-dihydro-benzo[b]thiepins. It was demonstrated that the use of nonracemic allyl carbamates enables the synthesis of enantioenriched benzo-fused seven-membered heterocycles. Finally, it was shown that further functionalization of the obtained structures allows access to pharmacologically active 5-amino-substituted 2,3,4,5-tetrahydro-1-benzo[b]oxepine scaffolds.

Full text of DOI:10.1021/acs.joc.6b01691

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Article
The synthesis of 5-amino-dihydrobenzo[b]oxepines
and 5-amino-dihydrobenzo[b]azepines via Ichikawa
rearrangement and ring-closing metathesis
Monika Chwastek, Micha# Pieczykolan, and Sebastian Stecko
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01691 • Publication Date (Web): 30 Aug 2016
Downloaded from http://pubs.acs.org on September 5, 2016
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The synthesis of 5ꢀaminoꢀdihydrobenzo[b]oxepines and 5ꢀaminoꢀ
dihydrobenzo[b]azepines via Ichikawa rearrangement and ringꢀclosing
metathesis
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Monika Chwastek, Michał Pieczykolan, and Sebastian Stecko*
Institute of Organic Chemistry, Polish Academy of Sciences
Kasprzaka 44/52, 01-224 Warsaw, Poland
eꢀmail: sebastian.stecko@icho.edu.pl
Graphical abstract
Abstract
The combination of Ichikawa’s domino reaction and a ringꢀclosing metathesis
reaction of allyl carbamates is presented as a method for the preparation of 5ꢀaminoꢀ
substituted 2,5ꢀdihydroꢀbenzo[b]oxepines, 2,5ꢀdihydroꢀbenzo[b]azepines and 2,5ꢀ
dihydroꢀbenzo[b]thiepins. It was demonstrated that the use of nonꢀracemic allyl
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carbamates enables the synthesis of enantioenriched benzoꢀfused sevenꢀmembered
heterocycles. Finally, it was shown that further functionalization of the obtained
structures allows access to pharmacologically active 5ꢀaminoꢀsubstituted 2,3,4,5ꢀ
tetrahydroꢀ1ꢀbenzo[b]oxepine scaffolds.
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Keywords
[
3,3]ꢀSigmatropic rearrangements, Ichikawa rearrangement, ringꢀclosing metathesis,
7ꢀmembered heterocycles.
Introduction
Benzannulated heterocycles constitute the core structure of numerous biologically
1
active compounds which display a wide range of pharmacological activities. One of
the most important classes of this family are benzodiazepines and benzothiazepines
which have been established as highly valuable scaffolds for medicinal chemistry and
drug development. Therefore, a lot of effort has been made in the last decades to
develop efficient strategies for the synthesis of structurally diverse libraries of these
1,2,3,4
molecules.
In contrast, dihydroꢀ1ꢀbenzoxepines and –benzazepines have received much
less attention despite numerous reports on their interesting and promising bioactivity
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towards various targets. For example, radualanin A (1) possesses antibiotic activity
whereas pterulone (2) is a fungal metabolite which inhibits eukaryotic respiration (Fig.
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1
). Another example is a group of benzooxepines which belong to the heliannuol
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family (3ꢀ5) and display allelipathic activity. A large group of 1ꢀbenzazepines have
been identified as nonꢀpeptide vasopressin 2 receptor antagonists (Fig. 2), for
example tolvaptan (6), and its analogues fedovapagon (7) and lixivaptam (8). Other
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structures have been reported to possess activity against enzymes (e.g.
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17,18
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ion channels (e.g. 10), and receptors.
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Figure 1. Structures of naturally occurring and biologically active 1ꢀbenzoxepines.
Figure 2. Structures of naturally occurring and biologically active 1ꢀbenzazepines.
Among this class of biomolecules, 5ꢀaminoꢀ1ꢀbenzoxepines and 5ꢀ
aminobenzazepines are an interesting subꢀgroup (Fig. 3). For example, mozavaptan
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7aꢀf
(11) and its analogues are nonꢀpeptide vasopressin 2 receptor antagonists.
Evacetrapib (12) is a potent cholesteryl ester transfer protein (CETP) inhibitor, which
transfers and thereby increases HDL and lowers LDL levels and as a result may
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modify the risk of cardiovascular disease.
Other interesting examples are:
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hypotensive agent 13, Src SH2 domain inhibitor 14, potassium channel activator
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5 or acetylꢀCoA cholesterol Oꢀacyl transferase (ACAT) inhibitor 16.
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Figure 3. Structures of several biologically active 5ꢀaminoꢀsubstituted 1ꢀ
benzoxepines and 1ꢀbenzazepines.
Due to their widespread occurrence and extensive utilization as building
blocks in pharmaceuticals, efficient and diversityꢀoriented synthetic protocols for the
preparation of 1ꢀbenzoxepines and 1ꢀbenzazepines are highly desirable. Typical
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approaches involve the formation of the 7ꢀmembered ring , for instance by Friedelꢀ
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Crafts type cyclization,
ringꢀclosingꢀmetathesis,
transition metalꢀcatalyzed
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cyclizations
or via substitution/condensation and introduction of the amino
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function at the Cꢀ5 position, for example via the Mitsunobu reaction, allylic
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amination
or imine allylation. This also includes strategies based on the
combination of the Claisen rearrangement of allyl phenyl ethers followed by Oꢀ
allylation and a ringꢀclosing metathesis (RCM) reaction which have found numerous
5,31,26, 32
applications in the total synthesis of natural products.
Recently, Sutherland
and coꢀworkers have shown the use of Overman rearrangement/RCM in the
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synthesis of 5ꢀaminoꢀ1ꢀbenzo[b]oxepines. However, in this case the rearrangement
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step requires harsh reaction conditions (reflux in xylene for 18ꢀ24h ), that is a
serious drawback of such approach, especially for sensitive molecules.
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Hence, as part of our program aimed at the application of cyanateꢀtoꢀ
isocyanate rearrangement in the synthesis of biologically active molecules, we
decided to ascertain whether this process, in combination with subsequent ringꢀ
closing metathesis, can be an attractive tool for the formation of benzoꢀfused sevenꢀ
membered heterocycles – either benzoxepines or benzazepines (Scheme 1). It
needs to be stressed that the transformation of the double bond in 17, for example
through its hydrogenation or oxidation, should enable the access to a broad range of
functionalized 5ꢀaminoꢀ1ꢀbenzoxepine or 5ꢀaminoꢀ1ꢀbenzazepine scaffolds present in
a wide range of pharmacologically active compounds such as those presented in Fig.
3.
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Scheme 1
Results and discussion
The synthesis of 5ꢀaminoꢀdihydroꢀ1ꢀbenzo[b]oxepines. Our efforts were primarily
focused on developing efficient access to 5ꢀaminoꢀdihydroꢀ1ꢀbenzooxepines. The
study began with the preparation of a series of 2ꢀallyloxyꢀcinnamyl carbamates 21aꢀn
which are direct precursors of allyl cyanates. Carbamates 21 were synthesized
starting from easily available salicylaldehydes or salicylic acids which were converted
into the corresponding allyl alcohols 20aꢀn in high overall yields, as presented in
Scheme 2. These alcohols were converted into allyl carbamates 21aꢀn by treatment
with trichloroacetyl isocyanate (TCAI) and subsequent hydrolysis. All of these
compounds were obtained in high yields with one exception. Under the described
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conditions carbamate 21i was obtained with very poor yield which did not exceed
10%. This compound was quite unstable under the reaction conditions as well as
during the further workꢀup and purification. It was particularly surprising since other
MeOꢀsubstituted carbamates (20h, 20j and 20k) were synthesized and isolated
without any problems.
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Modification of reaction conditions, such as lowering the reaction temperature
or the addition of a tertiary amine did not bring any improvement, neither did the
change of the manner of isolation and purification. Finally, carbamate 21i was
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prepared by using the Ichikawa’s protocol. Thus, alcohol 20i was heated with
phenyl carbamate in toluene in the presence of 20 mol% of dibutyltin maleate. After
3.5 h complete conversion of the starting material was achieved and the product was
isolated and chromatographed on florisil (50% yield). The reaction time was crucial in
this case; its extension to 12 h resulted in significant decrease of the yield to ca. 35%
along with increase of the amount of side products.
Scheme 2. Reagents and conditions: (a) allyl bromide, K
2 3
CO , DMF, 70ꢀ90%; (b) in
the case of the synthesis of carbamates 21f,g and k: i. allyl bromide, K CO , DMF,
2
3
77ꢀ94%; (c) LiAlH
4
, THF, –10 °C, 66ꢀ71%; (d) PCC, CH
2
2
Cl , rt, 82ꢀ87%; e)
(EtO)
2
P(O)CH
2
COOEt, NaH, THF, rt, 80ꢀ96% (f) DIBALꢀH, CH
2
Cl
2
, –78 °C, 60ꢀ95%;
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2 2 2 3
(g) i. TCAI, CH Cl , rt, ii. aq. K CO , MeOH, rt, 60ꢀ96% (2 steps); (h) in the case of
the synthesis of allyl carbamate 21i: phenyl carbamate, dibutyltin maleate (20 mol%),
PhMe, 90 °C, 50%.
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Carbamate 21a was utilized as a model substrate for subsequent
transformations. Its treatment with trifluoroacetic anhydride (TFAA) in the presence of
Et N resulted in the formation of allyl cyanate 22 which spontaneously underwent
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[
3,3]ꢀsigmatropic rearrangement to allyl isocyanate 23 (Scheme 3). The latter was not
isolated but directly treated with MeOH in the presence of a catalytic amount of
Bu SnOMe to provide carbamate 24a in 90% overall yield after 3 steps.
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Scheme 3. Reagents and conditions: (a) TFAA, Et N, THF, 0 °C to rt, 1h; (b) MeOH,
Bu SnOMe, THF, rt, 90% (overall after 3 steps); (c) Grubbs II catalyst (5 mol%),
3
DCE, 50 °C, 84%.
Using the optimized conditions, we explored the scope of the investigated
transformation (Scheme 4), and carbamates 21bꢀn were subjected to the
dehydration/rearrangement/addition sequence to provide the corresponding
carbamates 23bꢀn. The investigated approach was found to be general for various
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carbamates. As can be seen from the examples presented in Scheme 4, the
rearrangement proceeded well for substrates bearing either electronꢀdonating or
electronꢀwithdrawing groups. The location of the substituent in the phenyl ring,
particularly of the same one, showed no significance in reactivity giving the target
products. In the case of isomeric products the yields were comparable.
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Scheme 4
The formation of the isocyanate intermediate (e.g. 23) during the
rearrangement is a crucial advantage of the studied synthetic approach. Further
derivatization of allyl isocyanates opens an access to a broad range of Nꢀ
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functionalized allylamines by using various nucleophilic agents. Moreover, the
addition of the nucleophile to the isocyanate can be effected directly in a oneꢀpot
manner without its prior isolation (Scheme 5). Thus, the replacement of
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MeOH/Bu SnOMe by tꢀBuOLi or BnOLi enabled the synthesis of NꢀBocꢀ and NꢀCbzꢀ
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protected allylamines 24o and 24p, respectively. The isocyanate intermediate can be
also trapped directly by a Grignard reagent to provide the corresponding amides, for
instance 24q or 24r. Finally, direct treatment of intermediate 23 with BnNH or
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morpholine led to ureas derivatives 24s and 24t.
Scheme 5
In the final step, carbamates 24aꢀt were subjected to the metathesis reaction
to provide benzannulated products 25aꢀt. The cyclization was performed in the
presence of 5 mol% of the Grubbs II catalyst in dichloroethane at 50 °C (Scheme 6).
In most cases the reaction proceeded smoothly and took 2ꢀ3 h until completion. Only
the cyclization of urethanes 24s and 24t into benzoxepines 25s and 25t,
respectively, required longer reaction time (ca. 6 h) and the addition of another
portion of the catalyst after 3 h to achieve complete conversion of the starting
material.
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Scheme 6
The synthesis of 5ꢀaminoꢀ1ꢀbenzo[b]azepines. Encouraged by the successful
results of the synthesis of 5ꢀaminoꢀ1ꢀbenzoxepines via the combination of the
Ichikawa reaction and ringꢀclosing metathesis, we decided to apply this approach to
the synthesis of selected 5ꢀaminoꢀ1ꢀbenzazepines.
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Following the reaction sequence described above for benzoxepines, several
carbamates of type 30 were prepared starting from 2ꢀaminobenzaldehydes 26aꢀe, as
shown in Scheme 7.
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Scheme 7. Reagents and conditions: (a) allyl bromide, NaH, DMF, rt; (b)
(
EtO)
2
P(O)CH
2
2 2
COOEt, NaH, THF, rt; (c) DIBALꢀH, CH Cl , –78 °C; (d) i. TCAI,
CH
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Cl
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, rt, ii. aq. K
2
CO , MeOH, rt.
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3 3
Their treatment with TFAA/Et N followed by the addition of MeOH/Bu SnOMe
provided the desired rearrangement products (31aꢀd) with high overall yields after 3
steps (Scheme 8). This process proceeded efficiently also when other nucleophilic
agents were used to trap the isocyanate intermediate (31eꢀg).
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Scheme 8
Finally, dienes 31aꢀg were subjected to the ringꢀclosing metathesis reaction
under the previously described conditions to provide the corresponding 5ꢀaminoꢀ
benzazepines 32aꢀg with good yields (Scheme 9).
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Scheme 9
In 1995, Festal and coꢀworkers reported that sulfur analogues of 5ꢀaminoꢀ
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benzoxepine 16 are also potential ACAT inhibitors (e.g. 33). This inspired us to
examine whether the studied Ichikawa rearrangement/RCM approach may be
applied in the synthesis of 5ꢀaminoꢀbenzo[b]thiepin scaffold. For this purpose
thiosalicylic acidꢀderived allyl alcohol 34 was converted into allyl carbamate 35. This
compound was rearranged to 36 in 73% yield under standard conditions (Scheme
1
0). Unfortunately, despite many attempts the final ringꢀclosing metathesis reaction
catalyzed by the Grubbs II catalyst under various conditions failed. The replacement
of the Grubbs II catalyst by other ruthenium complexes also did not bring any
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change. Each time only the starting material was observed along with slight amounts
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46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 10. Reagents and conditions: (a) i. TCAI, CH
1% (2 steps); (b) i. TFAA, Et N, THF; ii. Bu SnOMe (10 mol%), MeOH, 73% (3
steps); (c) mꢀCPBA, CH Cl , rt, 81%; d) Grubbs II cat. (5 mol%), DCE, 50 °C, 90%.
2 2 2 3
Cl , rt; ii. aq. K CO , MeOH, rt,
8
3
3
2
2
To overcome this problem the sulfur atom in 36 was selectively oxidized to
sulfone 38. Now, the ringꢀclosing metathesis reaction proceeded smoothly and
provided the desired bicyclic product 39 in 90% yield (Scheme 10). It would be
expected that the sulfone moiety in 39 could be reduced to the sulfide by known
35
procedures.
The synthesis of nonꢀracemic 5ꢀaminoꢀ1ꢀbenzoxepines and 5ꢀaminoꢀ1ꢀ
benzazepines. In a continuation of our studies, we focused our interests on the
synthesis of nonꢀracemic 5ꢀaminoꢀ1ꢀbenzooxepines and 5ꢀaminoꢀ1ꢀbenzazepines.
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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
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5
5
5
5
5
5
5
5
5
5
6
Since the Ichikawa rearrangement is a spontaneous nonꢀcatalytic process, it cannot
be performed in an enantioselective fashion by the use of a chiral transition metal
36
complex as is possible in the case of an asymmetric Overman rearrangement.
However, due to the concerted course of the sigmatropic transformation proceeding
through a cyclic transition state, stereoselective generation of a new stereogenic
center can be achieved by efficient chirality transfer. This can be accomplished when
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
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
37
a nonꢀracemic starting allyl carbamate is applied. Very recently, we have shown
that such an approach is a very useful tool for the preparation of enantiomerically
3
8
enriched allylamines and therefore decided to use the same approach in the current
studies (Scheme 11).
Scheme 11
Our efforts were primarily focused on the synthesis of the required type 40
nonꢀracemic allyl alcohols. Initially, an asymmetric reduction of model enone 41 to
3 2
allyl alcohol 42 was investigated (Table 1). The CBS reduction of 41 with BH ꢁMe S
in the presence of (S)ꢀ2ꢀmethylꢀCBSꢀoxazaborolidine provided (R)ꢀ42 in poor 40%
yield (complete conversion of starting material) and with low enantioselectivity (e.e.
43%). The decrease of reaction temperature did not improve the level of the
selectivity but suppressed the reduction. The replacement of borane with
catecholborane gave only traces of the desired product. Asymmetric hydrogenation
39
of 41 with hydrogen in the presence of a Noyoriꢀtype catalyst (entry 3) resulted in
complete decomposition of the starting material. Alterative asymmetric hydrogen
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0
transfer reduction of 41 catalyzed by Ru(pꢀcymene)(S,S)ꢀTsꢀDPEN complex again
gave only traces of the desired product (Table 1, entry 4). Alcohol (S)ꢀ42 was
obtained in 43% yield (e.e. 50%, entry 5) when HCOOH:Et
3
N (5:2) complex was
41
applied as the hydrogen source. The reduction of 41 with (EtO) MeSiH in the
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
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30
31
32
33
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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
4
2
presence of a chiral copper complex, according to Lipshutz’s protocol, gave only
traces of the desired alcohol. An analogous reaction catalyzed by a chiral zinc
4
3
complex failed and only starting material was recovered. Stoichiometric reduction
44
with BINALꢀH was more efficient but still provided the desired product in moderate
6
0% yield, and the enantiomeric enrichment was not sufficient for further purposes.
Table. 1. Asymmetric reduction of enone 41.
O
OH
conditions
O
O
41
42
Yiel
d
a
e.e.
Ent.
Method
[
%]
[
%]
1
2
(S)ꢀMeꢀCBS, BH
3
—Me
2
S, –30 °C, THF, 14 h
40
trace
s
43(R)
(S)ꢀMeꢀCBS, catecholborane, –30 °C, THF, 14 h
ꢀ
3
4
RuCl [(S)ꢀDMꢀBINAP)][(S,S)ꢀDPEN], H (15 bar), iꢀPrOH
dc
ꢀ
ꢀ
2
2
RuCl(pꢀcymene)(S,S)ꢀTsꢀDPEN (10 mol%), KOH (10 mol%), iꢀ trace
PrOH, rt.
s
5
RuCl(pꢀcymene)(S,S)ꢀTsꢀDPEN (10 mol%), HCOOHꢀEt
3
N
43
50(S)
2 2
(5:2), CH Cl , rt
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5
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6
7
Zn(OAc)
2
, (5 mol%), ligand, DEMS, THF, 25 °C.
nr
trace
s
ꢀ
ꢀ
Cu(OAc) (3 mol%), (R)ꢀDTBMꢀSEGPHOS (3 mol%),
2
DEMS, Et
2
O, –25 °C
8
(S)ꢀBINALꢀH, THF, –78 °C to rt, 12 h
60
68(R)
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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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
a
determined by HPLC: Chiralpak ODꢀH, 10% IPA/hexanes, 1 mL/min, 254 nm; R
t
15.9 min (R isomer) and 27.4 min (S isomer); nd = not determined; nr = no reaction;
dc = decomposition of starting material.
The low efficiency of the synthesis of nonꢀracemic alcohol 42 forced us to
change the planned strategy of its preparation. Thus, enone 41 was reduced with
4 3
NaBH /CeCl to provide racꢀ42. This alcohol was subjected to a kinetic resolution
reaction by treatment with vinyl acetate in the presence of Candida antarctica lipase
to afford (S)ꢀ42 along with (R)ꢀacetate 43 (Scheme 12). The latter was next
hydrolyzed to furnish alcohol (R)ꢀ42. Both isomers were obtained with a good level of
enantioselectivity. In the same manner, nitrogen analogues (S)ꢀ45 and (R)ꢀ45 were
prepared (Scheme 12).
Scheme 12. Reagents and conditions: (a) CeCl
3 2 4
ꢁ7H O, NaBH , MeOH, rt; (b) vinyl
acetate, Candida antarctica lipase, pentane, MS 4Å, rt; (c) K CO , MeOH/H O (4:1),
2
3
2
rt.
1
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Independently, an alternative approach to nonꢀracemic alcohol 42, which is
outlined in Scheme 13, was investigated. New concept assumed coupling of 2ꢀ
iodophenol (48a) with commercially available (S)ꢀbutꢀ3ꢀynꢀ2ꢀol (47a) but only traces
of the desired product was obtained. Better results were obtained in the case of the
coupling reaction of 47a with Oꢀprotected 2ꢀiodophenol 48b; desired product 50 was
obtained in 30% yield only. The coupling proceeded more efficiently when both Oꢀ
protected starting marerials 47b and 48c were applied (84%). The product 49 was
10
11
12
13
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17
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23
24
25
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28
29
30
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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
then deacetylated by treatment with NH in MeOH, Oꢀallylated and desilylated to
provide 50 in 62% overall yield. Finally, hydroalumination of triple bond with LiAlH
4
,
followed by hydrolysis, gave (S)ꢀ42 in 85% yield (96.7% e.e.). This synthetic
approach let us also to confirm absolute configuration of alcohols 42 obtained by a
kinetic resolution.
Scheme 13. Reagents and conditions: (a) Pd(PPh
Et N, THF, rt, 84%; (b) i. NH , MeOH, rt, ii. allyl bromide, K
THF, rt, 62% (3 steps); (c) LiAlH , THF, rt, 85%.
3
)
2
Cl
2
(1 mol%), CuI (10 mol%),
3
3
2
CO , DMF, iii. TBAF,
3
4
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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 14. Reagents and conditions: (a) phenyl carbamate, dibutyltin maleate (20
mol%), PhMe, 90 °C; (b) i. TFAA, Et N, THF, 0 °C to rt, 1 h; ii. Bu SnOMe (10 mol%),
3
3
MeOH, rt; (c) Grubbs II cat. (5 mol%), DCE, 50 °C
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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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
With nonꢀracemic allyl alcohols in hand, we prepared the corresponding allyl
carbamates 51 and 52 by tinꢀcatalyzed transcarbamoylation with phenyl carbamate
34
(
Scheme 14). The previously used protocol based on treatment with TCAI gave the
desired carbamates 51 and 52 with lower yields (ca. 30ꢀ40%). Their sequential
dehydration/rearrangement/addition transformation provided compounds 53 and 54,
which were subjected to the final cyclization step. The RCM reaction catalyzed by the
Grubbs II catalyst gave the desired chiral benzannulated 7ꢀmembered heterocycles
55 and 56 in 77% and 74% yields, respectively (Scheme 14).
The application of the Ichikawa rearrangement/RCM sequence to the synthesis
of bioactive molecules. The final step of this research program was the
demonstration of the synthetic utility of the developed approach in the synthesis of
biologically active scaffolds.
The already mentioned cholesterol Oꢀacyl transferase (ACAT) is an enzyme
which plays an important part in intracellular cholesterol esterification, for instance in
24
the intestines or liver.
Its inhibitors are expected to prevent both
hypercholesterolemia and atherosclerosis. Among structurally different potential
ACAT inhibitors sevenꢀmembered heterocycles can be found, for instance the
already mentioned 5ꢀaminoꢀbenzoxepine 16. We decided to apply the reported
synthetic protocol in the total synthesis of compound 16. For this purpose allyl alcohol
58 was prepared by modifying the previously reported protocol starting from methyl
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3
3b
4ꢀiodosalicylate and 4ꢀfluorophenylboronic acid (Scheme 15).
Alcohol 58 was
treated with TCAI followed by basic hydrolysis to give allyl carbamate 59. Compound
9 was then treated with TFAA in the presence of Et N to provide the corresponding
5
3
isocyanate. This was directly treated with nꢀhexylmagnesium bromide to afford
carbamate 60 in 70% yield after 3 steps. In this manner the sideꢀchain of the target
compound was directly established. In the next step diene 60 was treated with the
Grubbs II catalyst to afford ringꢀclosing metathesis product 61 in 86% yield. Then, the
double bond in 61 was hydrogenated (62), followed by the reduction of the amide
10
11
12
13
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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
function by LiAlH
directly treated with 2,4ꢀdifluorophenyl isocyanate to provide the final product 16 in
3% yield (Scheme 15).
4
. The resulting amine 63, after simple aqueous workꢀup, was
7
Scheme 15. Reagents and conditions: a) 4ꢀfluorophenylboronic acid, Pd(dppf)Cl
mol%), Cs CO (2 eq.), 1,4ꢀdioxane/H O, 80 °C, 14 h, 85%; (b) i. TCAI, CH Cl , rt, ii.
aq. K CO , MeOH, rt, 79% (2 steps); (c) i. TFAA, Et N, THF, 0 °C to rt, 1 h; ii. nꢀ
2
(5
2
3
2
2
2
2
3
3
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2
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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
hexylMgBr, THF, 0 °C to rt, 6 h, 70% (overall after 3 steps); d) Grubbs II cat. (3
mol%), DCE (c 0.01M), 86%; e) H , 10% Pd/C, AcOEt, 96%; f) LiAlH , THF, 60 °C; g)
2
4
2,4ꢀdifluorophenyl isocyanate, THF, rt, 73%.
0
1
2
3
4
5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
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5
6
7
8
9
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2
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
20
Another interesting target was guanidine derivative 13, a hypotensive agent.
To obtain the target 13, carbamate 21f was subjected to the Ichikawa domino
process (Scheme 16). The isocyanate intermediate was trapped with TMSOLi
45
followed by treatment with TBAF to provide free allylamine 64. Guanylation of 64
46,33b
with diꢀBocꢀpyrazoleꢀ1ꢀcarboximidamide (65)
2% yield. This compound was then subjected to Grubbs II complex catalyzed RCM
reaction to provide the corresponding cyclic product 67 in 77% yield. Hydrogenation
of double bond in 67 in the presence of the Pd(OH) (10 mol%) provided product 68
88%) which can serve as a direct precursor of hypotensive agent 13 (Scheme 16).
We also investigated an alternative approach in which the guanylation was
gave guanidine derivative 66 in
7
2
33b
(
planned to be performed at the late stages of the synthesis after the formation of the
oxepine ring (Scheme 16). Thus, compound 21f was transformed into NꢀCbz
allylamine 69 (93% after 3 steps). In the presence of the Grubbs II catalyst it was
cyclized to compound 70 in 64% yield. In the next step, simultaneous hydrogenation
of the double bond and deprotection of the amine function to give amine 71 were
planned. Disappointingly, the hydrogenation in the presence of Pd/C or Pd(OH)
2
resulted in dehalogenation and partial degradation of the 7ꢀmembered ring.
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34
35
36
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 16. Reagents and conditions: a) i. TFAA, Et
THF, rt, 3 h; iii. TBAF, THF, rt, 73% (4 steps); b) 65, DMF, rt, 72%; c) Grubbs II
catalyst (2×3 mol%), DCE, 60 °C, 77%; d) H , Pd(OH) , AcOEt, rt, 1.5 h, 88%; e) i.
TFAA, Et N, THF, 0 °C, 1 h; ii. BnOLi, THF, rt, 93% (overall after 3 steps); f) Grubbs
II catalyst (5 mol%), DCE, 64%; g) H , 10% Pd/C, AcOEt, rt.
3
N, THF, 0 °C, 1 h; ii. TMSOLi,
2
2
3
2
Finally, the presented approach can also be applied in the synthesis of
47
compounds such as 72 which show activity as CCR1 antagonists (Scheme 17). As
showed in Scheme 17, the treatment of the isocyanate intermediate 73 generated
47
from carbamate (S)ꢀ42 with proline amide 74, provided the product 75 in 65% yield.
Upon treatment with the Grubbs II catalyst, diene 75 was cyclized to product 76
(76%). Further transformation of 76 should provide 72ꢀtype molecules (Scheme 17).
In addition, the use of (R)ꢀ42, following the same reaction sequence, should open
access to their diastereoisomeric forms.
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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
Cl
N
O
R
HN
N
7
2
O
R or S
Cl
Cl
O
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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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
C
N
O
N
N
N
a
O
N
b
O
(
S)ꢀ42
O
O
N
H
O
N
O
H
7
3
75
76
N
H
Cl
H
N
Cl
O
7
4
Scheme 17. Reagents and conditions: (a) TFAA, Et
3
N, THF, 0 °C, 1 h; ii. amine 74,
Et N, THF, 65% (3 steps); (b) Grubbs II catalyst (5 mol%), DCE, 76%.
3
Conclusions
In summary, a general method for the preparation of 5ꢀaminoꢀ2,5ꢀdihydroꢀ1ꢀ
benzooxepines, ꢀazepines and ꢀthiepins was reported. The presented approach is
based on oneꢀpot dehydration/rearrangement/addition reaction sequence (Ichikawa
rearrangement) followed by the ringꢀclosing metathesis reaction of readily available
2
ꢀallyloxyꢀ, NꢀTsꢀ2ꢀallylaminoꢀ or 2ꢀallylthioꢀcinnamyl carbamate derivatives. These
starting materials can be easily prepared from readily available 2ꢀhydroxyꢀ, 2ꢀaminoꢀ
or 2ꢀmercaptoꢀbenzaldehydes. The presented method allows the preparation of
diverse libraries of 5ꢀamino benzannulated 7ꢀmembered heterocycles.
3
3b
The reported approach is complementary to previously reported method of
preparation of of 5ꢀaminoꢀ2,5ꢀdihydroꢀ1ꢀbenzooxepines via Overman
rearrangement/RCM sequence. However, the use of Ichikawa reaction has several
significant advantages. In contrast to Overman reaction, this transformation proceeds
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3b
under milder condition (at 0 °C/rt for 1h vs. reflux in xylene for 18ꢀ24h ) and does
not require any catalyst. The utility of the Ichikawa reaction as a key step enables the
direct formation of Nꢀfunctionalized allylamines in a oneꢀpot manner by trapping the
intermediate isocyanate by selected nucleophilic agents. The use of nonꢀracemic
starting allyl carbamates, which can be prepared either by enzymatic kinetic
resolution or coupling reaction, enables the access to enantiomericallyꢀenriched
heterocycles. Finally, the synthetic utility of the reported approach was illustrated by
the synthesis of selected biologically active 5ꢀaminoꢀ1,2,3,4ꢀtetrahydroꢀ
benzo[b]oxepines.
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
Experimental section
Allylation of salicylaldehydes. General procedure: To a stirred solution of
2 3
salicylaldehyde (1 eq.) in anhydrous DMF (0.7 M) was added anhydrous K CO (1.5
eq.) and allyl bromide (1.5 eq.). The resulting mixture was stirred until complete
consumption of the starting material was achieved, as determined by TLC. The postꢀ
reaction mixture was then diluted with AcOEt and washed with water (3×) and brine.
The organic layer was dried over anhydrous Na SO , filtered and concentrated to
2
4
dryness in vacuo. The product was isolated by flash column chromatography using
AcOEt/hexanes mixtures as the eluent.
2
ꢀ(allyloxy)benzaldehyde (18a): yield 15.75 g (78%) starting from 15 g of
1
salicylaldehyde; colorless oil; H NMR (400 MHz, CDCl
3
) δ: 10.48 (s, 1H), 7.81ꢀ7.71
(
m, 1H), 7.52ꢀ7.42 (m, 1H), 7.00ꢀ6.86 (m, 2H), 6.09ꢀ5.96 (m, 1H), 5.44ꢀ5.36 (m, 1H),
13
5.31ꢀ5.24 (m, 1H), 4.70ꢀ4.50 (m, 2H); C NMR (101 MHz, CDCl
3
) δ: 189.5, 160.9,
1
35.80, 135.79, 132.4, 128.3, 125.1, 120.8, 117.9, 112.9, 69.1; FTIR (film) v: 2922,
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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
2856, 1687, 1599, 1488, 1457, 1396, 1286, 1241, 1224, 1162, 995, 843, 758 cm ;
HRMS (EI) m/z calcd for C10 [M] 162.0681; Found 162.0687.
10 2
H O
2
ꢀ(allyloxy)ꢀ5ꢀmethylbenzaldehyde (18b): yield 6.29 g (99%) starting from 5 g of 5ꢀ
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
methylsalicylaldehyde; colorless oil; H NMR (400 MHz, CDCl
d, J 2.4 Hz, 1H), 7.27 (ddd, J 8.5, 2.4, 0.6 Hz, 1H), 6.83 (d, J 8.5 Hz, 1H), 6.02 (ddt,
J 17.3, 10.4, 5.1 Hz, 1H), 5.40 (dq, J 17.3, 1.7 Hz, 1H), 5.27 (dq, J 10.6, 1.4 Hz, 1H),
3
) δ: 10.46 (s, 1H), 7.58
(
13
4.57 (dt, J 5.2, 1.6 Hz, 2H), 2.25 (s, 3H); C NMR (101 MHz, CDCl
3
) δ: 189.7, 159.0,
1
2
36.4, 132.6, 130.2, 128.3, 124.8, 117.8, 112.9, 69.2, 20.2; FTIR (film) v: 2923, 2861,
ꢀ1
760, 1685, 1612, 1495, 1285, 1247, 1162, 1018, 996, 940, 812, 731 cm ; HRMS
[M] 176.0837; Found 176.0842.
(EI) m/z calcd for C11
H
12
O
2
2ꢀ(allyloxy)ꢀ4ꢀmethylbenzaldehyde (18c): yield 6.65 g (77%) starting from 6.65 g
1
of 4ꢀmethylsalicylaldehyde; colorless oil; H NMR (400 MHz, CDCl
3
) δ: 10.43 (d, J 0.8
Hz, 1H), 7.69 (d, J 7.9 Hz, 1H), 6.82ꢀ6.77 (m, 1H), 6.74 (s, 1H), 6.04 (ddt, J 17.3,
0.4, 5.1 Hz, 1H), 5.42 (dq, J 17.3, 1.7 Hz, 1H), 5.30 (dq, J 10.6, 1.4 Hz, 1H), 4.60
1
13
3
(dt, J 5.1, 1.6 Hz, 2H), 2.35 (s, 3H); C NMR (101 MHz, CDCl ) δ: 189.2, 161.0,
147.3, 132.5, 128.3, 122.9, 121.8, 117.8, 113.4, 69.0, 22.3; FTIR (film) v: 3077, 3020,
ꢀ1
2
985, 2923, 2859, 2762, 1683, 1606, 1418, 1258, 814 cm ; HRMS (ESIꢀTOF) m/z
+
calcd for C H O Na [M+Na ] 199.0735; Found 199.0734.
11
12
2
2
ꢀ(allyloxy)ꢀ3ꢀmethylbenzaldehyde (18d): yield 6.16 g (95%) starting from 5 g of 3ꢀ
1
methylsalicylaldehyde; yellowish oil; H NMR (400 MHz, CDCl
3
) δ: 10.36 (d, J 0.7 Hz,
1H), 7.67 (dd, J 7.7, 1.3 Hz, 1H), 7.43 (ddd, J 7.5, 1.8, 0.7 Hz, 1H), 7.12 (t, J 7.6 Hz,
1
1
1
H), 6.09 (ddt, J 17.1, 10.4, 5.7 Hz, 1H), 5.41 (dq, J 17.1, 1.5 Hz, 1H), 5.32ꢀ5.26 (m,
13
H), 4.45 (dt, J 5.7, 1.3 Hz, 2H), 2.33 (s, 3H); C NMR (101 MHz, CDCl3) δ: 190.4,
60.4, 137.5, 132.7, 132.4, 129.5, 126.3, 124.4, 118.6, 76.5, 15.8; FTIR (film) v:
3080, 3017, 2981, 2923, 2860, 27, 52, 1695, 1682, 1589, 1470, 1391, 1248, 1203,
2
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ꢀ
1
+
12 2
1085, 986, 921, 783, 768 cm ; HRMS (ESIꢀTOF) m/z calcd for C11H O Na [M+Na ]
199.0735; Found 199.0737.
2
ꢀ(allyloxy)ꢀ5ꢀchlorobenzaldehyde (18e): yield 5.96 g (95%) starting from 5 g of 5ꢀ
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
chlorosalicylaldehyde; yellowish oil; H NMR (400 MHz, CDCl
3
) δ: 10.44 (s, 1H), 7.77
(
d, J 2.7 Hz, 1H), 7.45 (dd, J 8.9, 2.8 Hz, 1H), 6.92 (d, J 8.9 Hz, 1H), 6.05 (ddt, J
17.2, 10.5, 5.2 Hz, 1H), 5.43 (dq, J 17.3, 1.5 Hz, 1H), 5.34 (dq, J 10.6, 1.5 Hz, 1H),
13
4.64 (dt, J 5.2, 1.5 Hz, 2H); C NMR (101 MHz, CDCl
3
) δ: 188.3, 159.3, 135.3,
1
1
2
32.0, 127.9, 126.6, 126.0, 118.5, 114.6, 69.6; FTIR (film) v: 1685, 1596, 1480, 1393,
ꢀ1
+
271, 1181 cm ; HRMS (ESIꢀTOF) m/z calcd for C11
13 3
H O ClNa [M+MeOH+Na ]
51.0451; Found 251.0448.
2ꢀ(allyloxy)ꢀ5ꢀmethoxybenzaldehyde (18h): yield 5.95 g (94%) starting from 5 g of
1
5
7
1
ꢀmethoxysalicylaldehyde; colorless oil; H NMR (400 MHz, CDCl
3
) δ: 10.49 (s, 1H),
.32 (d, J 3.3 Hz, 1H), 7.10 (dd, J 9.1, 3.3 Hz, 1H), 6.93 (d, J 9.1 Hz, 1H), 6.05 (ddt, J
7.2, 10.5, 5.2 Hz, 1H), 5.42 (dq, J 17.3, 1.6 Hz, 1H), 5.31 (dq, J 10.5, 1.4 Hz, 1H),
13
4.60 (dt, J 5.2, 1.5 Hz, 2H), 3.79 (s, 3H); C NMR (101 MHz, CDCl
3
) δ: 189.5, 155.7,
153.8, 132.6, 125.4, 123.4, 118.0, 114.9, 110.3, 70.0, 55.8; FTIR (film) v: 3079, 3001,
2
941, 2910, 2864, 2837, 1686, 1494, 1425, 1394, 1279, 1217, 1162, 1039, 935, 815,
ꢀ1
+
7
12 3
24, 587 cm ; HRMS (ESIꢀTOF) m/z calcd for C11H O Na [M+Na ] 215.0684;
Found 215.0682.
2ꢀ(allyloxy)ꢀ4ꢀmethoxybenzaldehyde (18i): yield 6.09 g (96%) starting from 5 g of
1
4
7
1
ꢀmethoxysalicylaldehyde; colorless oil; H NMR (400 MHz, CDCl
3
) δ: 10.31 (s, 1H),
.77 (d, J 8.7 Hz, 1H), 6.53ꢀ6.48 (m, 1H), 6.40 (d, J 2.2 Hz, 1H), 6.03 (ddt, J 17.3,
0.5, 5.1 Hz, 1H), 5.42 (dq, J 17.3, 1.6 Hz, 1H), 5.29 (dq, J 10.5, 1.4 Hz, 1H), 4.61ꢀ
13
4.56 (m, 2H), 3.81 (s, 3H); C NMR (101 MHz, CDCl
3
) δ: 188.1, 166.0, 162.6, 132.3,
130.4, 119.2, 118.0, 106.1, 99.0, 69.1, 55.6; FTIR (film) v: 3082, 3010, 2940, 2854,
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5
5
5
5
5
5
5
5
6
ꢀ
1
2766, 1678, 1602, 1502, 1442, 1294, 1261, 1201, 1171, 1114, 1004, 824 cm ;
+
HRMS (ESIꢀTOF) m/z calcd C H O Na [M+Na ] 215.0686; found 215.0676.
11
12
3
2
3
7
ꢀ(allyloxy)ꢀ3ꢀmethoxybenzaldehyde (18j): yield 5.73 g (85%) starting from 5 g of
1
ꢀmethoxyꢀsalicylaldehyde; colorless oil; H NMR (500 MHz, CDCl
3
) δ: 10.44 (s, 1H),
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
.41 (dd, J 7.3, 2.1 Hz, 1H), 7.17ꢀ7.10 (m, 2H), 6.07 (ddt, J 16.5, 10.4, 6.1 Hz, 1H),
13
5.38ꢀ5.33 (m, 1H), 5.28ꢀ5.24 (m, 1H), 4.66 (d, J 6.0 Hz, 2H), 3.90 (s, 3H); C NMR
126 MHz, CDCl ) δ: 190.3, 152.9, 151.1, 133.1, 130.1, 124.0, 118.9, 118.7, 117.9,
(
3
7
5.1, 55.9; FTIR (film) v: 3084, 3011, 2941, 2863, 1692, 1584, 1481, 1267, 1250,
ꢀ
1
+
1
12 3
066, 983, 786 cm ; HRMS (ESIꢀTOF) m/z calcd for C11H O Na [M+Na ] 215.0684;
found 215.0678.
ꢀ(allyloxy)ꢀ5ꢀnitrobenzaldehyde (18l): yield 6.12 g (98%) starting from 5 g of 5ꢀ
2
33b
1
nitroꢀsalicylaldehyde; white solid; m.p. 61ꢀ62 °C (Lit. 62ꢀ64 °C); H NMR (400 MHz,
CDCl ) δ: 10.50 (s, 1H), 8.71 (d, J 2.9 Hz, 1H), 8.41 (dd, J 9.2, 2.9 Hz, 1H), 7.11 (d, J
.2 Hz, 1H), 6.09 (ddt, J 17.3, 10.5, 5.3 Hz, 1H), 5.49 (dq, J 17.3, 1.6 Hz, 1H), 5.43
3
9
13
(dq, J 10.6, 1.3 Hz, 1H), 4.80 (dt, J 5.3, 1.5 Hz, 2H); C NMR (101 MHz, CDCl
3
) δ:
1
3
87.4, 164.6, 141.7, 131.0, 130.5, 124.9, 124.7, 119.5, 113.3, 70.2; FTIR (film) v:
ꢀ1
357, 3096, 2880, 1685, 1609, 1526, 1348, 1278, 1178, 988, 924, 835, 747 cm ;
NO [M] 207.0518; found 207.0520.
HRMS (EI) m/z calcd for C10
H
9
4
2ꢀ(allyloxy)ꢀ6ꢀmethoxyꢀ4ꢀnitrobenzaldehyde (18m): yield 5.9 g (98%) starting from
1
5
g of 6ꢀmethoxyꢀ4ꢀnitroꢀsalicylaldehyde; white solid, m.p. 82ꢀ83 °C; H NMR (400
MHz, CDCl
3
) δ: 10.35 (s, 1H), 7.63 (d, J 3.3 Hz, 1H), 7.57 (d, J 3.3 Hz, 1H), 6.13ꢀ6.00
(
m, 1H), 5.39 (dq, J 17.1, 1.4 Hz, 1H), 5.34 (dq, J 10.3, 1.0 Hz, 1H), 4.61 (dt, J 6.1,
13
1.2 Hz, 3H), 3.88 (s, 3H); C NMR (101 MHz, CDCl
3
) δ: 187.7, 155.5, 148.4, 144.8,
132.2, 131.6, 120.5, 117.1, 116.6, 79.1, 56.3; FTIR (film) v: 3083, 2974, 2949, 2886,
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ꢀ
1
2844, 1688, 1534, 1427, 1348, 1305, 1233, 1049, 945, 928, 784 cm ; HRMS (EI)
m/z calcd for C H NO [M] 237.0637; found 237.0636.
11
11
5
2
ꢀ(allyloxy)ꢀ1ꢀnaphthaldehyde (18n): yield 3.57 g (58%) starting from 5 g of 2ꢀ
1
hydroxyꢀ1ꢀnaphylaldehyde; yellow solid, m.p. 73ꢀ74 °C; H NMR (400 MHz, CDCl
3
) δ
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
0.94 (s, 1H), 9.30–9.26 (m, 1H), 8.00 (d, J 9.1 Hz, 1H), 7.75 (d, J 8.1 Hz, 1H), 7.61
(ddd, J 8.5, 6.9, 1.4 Hz, 1H), 7.41 (ddd, J 8.1, 6.9, 1.1 Hz, 1H), 7.23 (d, J 9.2 Hz, 1H),
6
1
1
.09 (ddt, J 17.3, 10.4, 5.2 Hz, 1H), 5.47 (dq, J 17.3, 1.7 Hz, 1H), 5.35 (dq, J 10.6,
13
3
.4 Hz, 1H), 4.77 (dt, J 5.2, 1.5 Hz, 2H); C NMR (101 MHz, CDCl ) δ: 192.0, 192.0,
63.1, 132.3, 131.5, 129.8, 128.6, 128.2, 125.0, 124.8, 118.3, 117.2, 113.9, 70.2;
FTIR (film) v: 2928, 2883, 2871, 1661, 1592, 1514, 1340, 1268, 1244, 1151, 1053,
ꢀ1
1
024, 1008, 955, 808, 757 cm ; HRMS (EI) m/z calcd for C14
found 212.0835.
Allyl 2ꢀ(allyloxy)ꢀ4ꢀfluorobenzoate: To a stirred solution of 4ꢀfluorosalicylic acid (5
g, 6.96 mmol) in anhydrous DMF (100 mL) were added anhydrous K CO (17.7 g,
12 2
H O [M] 212.0837;
2
3
128.11 mmol) and allyl bromide (10.07 g, 7.2 mL, 83.27 mmol). The resulting mixture
was stirred until complete consumption of the starting material was achieved, as
determined by TLC. The postꢀreaction mixture was then diluted with AcOEt and
washed with water (3×) and brine. The organic layer was dried over anhydrous
2 4
Na SO , filtered and concentrated to dryness in vacuo. The product was isolated by
flash column chromatography using 1% AcOEt/hexanes mixtures as the eluent to
afford 7.1 g (94%) of compound allyl 2ꢀ(allyloxy)ꢀ4ꢀfluorobenzoate as a colorless oil;
1
H NMR (400 MHz, CDCl ) δ: 7.88ꢀ7.78 (m, 1H), 6.64ꢀ6.59 (m, 2H), 6.06ꢀ5.91 (m,
3
2H), 5.47 (dq, J 17.2, 1.6 Hz, 1H), 5.39ꢀ5.30 (m, 1H), 5.26 (dq, J 10.6, 1.4 Hz, 1H),
13
5.21 (dt, J 10.5, 1.3 Hz, 1H), 4.78ꢀ4.71 (m, 2H), 4.58ꢀ4.51 (m, 2H); C NMR (101
MHz, CDCl ) δ: 167.2, 164.9 and 162.5 (d, JCꢀF 241.9 Hz), 160.3 and 160.2 (d, JCꢀF
3
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10.6 Hz), 133.9 and 133.8 (d, JCꢀF 10.9 Hz), 132.3, 132.0, 118.1, 117.9, 116.49 and
1
2
1
8
16.46 (d, JCꢀF 3.1 Hz), 107.4 and 107.2 (d, JCꢀF 21.7 Hz), 101.5 and 101.3 (d, JCꢀF
5.6 Hz), 69.7, 65.4; FTIR (film) v: 3087, 2988, 2939, 2884, 1731, 1706, 1681, 1609,
593, 1499, 1421, 1286, 1269, 1241, 1172, 1122, 1102, 1076, 1016, 997, 962, 932,
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
+
13 3
38, 770 cm ; HRMS (ESIꢀTOF) m/z calcd for C13H O FNa [M+Na ] 259.0746
found 259.0742.
Allyl 2ꢀ(allyloxy)ꢀ4ꢀchlorobenzoate: prepared in the same manner as allyl 2ꢀ
(allyloxy)ꢀ4ꢀfluorobenzoate; yield 6.16 g (77%) starting from 5.4 g of 4ꢀchlorosalicylic
1
acid; H NMR (400 MHz, CDCl
3
) δ: 7.78 (d, J 8.1 Hz, 1H), 7.00ꢀ6.93 (m, 2H), 6.10ꢀ
5.95 (m, 2H), 5.51 (dq, J 17.3, 1.6 Hz, 1H), 5.40 (dq, J 17.2, 1.3 Hz, 1H), 5.31 (dq, J
10.6, 1.4 Hz, 1H), 5.26 (dq, J 10.6, 1.3 Hz, 1H), 4.79 (dt, J 5.6, 1.3 Hz, 2H), 4.60 (dt,
13
J 4.9, 1.6 Hz, 2H); C NMR (101 MHz, CDCl ) δ: 165.0, 158.8, 139.2, 132.9, 132.1,
3
132.0, 120.6, 118.9, 118.2, 118.0, 114.1, 69.7, 65.6; FTIR (film) v: 3085, 3020, 2986,
2937, 2877, 1731, 1594, 1487, 1410, 1281, 1243, 1133, 1074, 999, 930, 901, 771
ꢀ1
+
cm ; HRMS (ESIꢀTOF) m/z calcd for C13
13 3
H O ClNa [M+Na ] 275.0451; found
275.0446.
Allyl 2ꢀ(allyloxy)ꢀ6ꢀmethoxybenzoate: prepared in the same manner as compound
allyl 2ꢀ(allyloxy)ꢀ4ꢀfluorobenzoate; yield 6.85 g (93%) starting from 5 g of 6ꢀ
1
methoxysalicylic acid; yellowish oil; H NMR (400 MHz, CDCl
3
) δ: 7.24 (t, J 8.4 Hz,
1H), 6.56ꢀ6.52 (m, 2H), 6.05ꢀ5.92 (m, 2H), 5.44ꢀ5.33 (m, 2H), 5.26ꢀ5.20 (m, 2H), 4.82
13
(
dt, J 5.6, 1.5 Hz, 2H), 4.54 (dt, J 5.0, 1.7 Hz, 2H), 3.81 (s, 3H); C NMR (101 MHz,
CDCl ) δ: 166.1, 157.4, 156.4, 132.8, 132.2, 130.9, 118.0, 117.2, 113.6, 105.4,
3
104.1, 69.4, 65.7, 56.0; FTIR (film) v: 33085, 3015, 2981, 2940, 2842, 1732, 1597,
ꢀ
1
1472, 1424, 1297, 1255,. 1106, 1071, 929, 785, 730 cm ; HRMS (ESIꢀTOF) m/z
+
calcd for C14
H
16
O
4
Na [M+Na ] 271.0946; found 271.0946.
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(
2ꢀ(allyloxy)ꢀ4ꢀfluorophenyl)methanol: To a solution of allyl 2ꢀ(allyloxy)ꢀ4ꢀ
fluorobenzoate (7.0 g, 29.63 mmol) in dry THF (100 mL) cooled to –10 °C was added
M soln. LiAlH in THF (35.56 mmol, 17.8 mL). After stirring for 30 min at –10 °C the
2
4
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
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41
42
43
44
45
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47
48
49
50
51
52
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58
59
60
reaction mixture was adjusted to rt and stirred at the same temperature until
complete consumption of the starting material was achieved, as determined by TLC
(ca. 2ꢀ3 h). Then reaction mixture was poured into 2M aq. NaOH and extracted with
Et O. The combined organic layers were dried over anhydrous Na SO , filtered and
2
2
4
concentrated to dryness in vacuo. The crude product was isolated by flash column
chromatography on silica gel (10% AcOEt/hexanes) to afford 3.73 g (69%) of (2ꢀ
1
(
allyloxy)ꢀ4ꢀfluorophenyl)methanol as a white solid; M.p. 53ꢀ54 °C H NMR (400 MHz,
CDCl ) δ: 7.28ꢀ7.18 (m, 1H), 6.68ꢀ6.57 (m, 2H), 6.10ꢀ5.97 (m, 1H), 5.41 (dq, J 17.3,
3
13
1
.5 Hz, 1H), 5.31 (dq, J 10.5, 1.9 Hz, 1H), 4.65 (s, 2H), 4.59ꢀ4.51 (m, 2H); C NMR
(
101 MHz, CDCl ) δ: 164.3 and 161.9 (d, JCꢀF 245.2 Hz), 157.4 and 157.3 (d, JCꢀF
3
10.2 Hz), 132.4, 129.6 and 129.5 (d, JCꢀF 10.1 Hz), 125.25 and 125.23 (d, JCꢀF 3.3
Hz), 118.0, 107.0 and 106.8 (d, JCꢀF 21.1 Hz), 100.1 and 99.9 (d, JCꢀF 26.0 Hz), 69.0,
19
6
1.2; F NMR (376 MHz, CDCl ) δ: ꢀ112.0; FTIR (film) v: 3361, 3085, 2926, 2874,
3
ꢀ1
1
11 2
610, 1503, 1421, 1277, 1152, 1012, 833 cm ; HRMS (EI) m/z calcd for C10H O F
[M] 182.0743; found 182.0746.
2ꢀ(allyloxy)ꢀ4ꢀchlorophenyl)methanol: prepared in the same manner as
(
compound (2ꢀ(allyloxy)ꢀ4ꢀfluorophenyl)methanol; yield 3.17 g (66%) starting from 6.1
1
g of allyl 2ꢀ(allyloxy)ꢀ4ꢀchlorobenzoate; white solid, m.p. 50ꢀ51 °C; H NMR (400
3
MHz, CDCl ) δ: 7.20 (d, J 8.0 Hz, 1H), 6.90 (dd, J 8.0, 1.9 Hz, 1H), 6.82 (d, J 1.9 Hz,
1H), 6.01 (ddt, J 17.3, 10.5, 5.2 Hz, 1H), 5.39 (dq, J 17.3, 1.6 Hz, 1H), 5.30 (dq, J
13
1
0.5, 1.4 Hz, 1H), 4.62 (s, 2H), 4.52 (dt, J 5.2, 1.5 Hz, 2H); C NMR (101 MHz,
29
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