Observations concerning the synthesis of heteroatom-containing 9-membered benzo-fused rings by ring-closing metathesis

Article abstract of DOI:10.1016/j.tet.2017.06.039

A set of benzo-fused dienes with a 1,9-relationship and containing a variety of nitrogen and oxygen heteroatoms was readily synthesized. These dienes were then treated with the Grubbs second generation catalyst with the aim of synthesizing the 9-membered benzannelated heterocycles containing two heteroatoms (either O,O, NR,NR or O,NR where R = Ts or Boc). As previously observed in the literature, many of the dienes did not give the expected ring-closed product. However, a number of the desired products did form, namely with the 1,2-dihydrobenzo[c][1,5]oxazonin-7(5H)-one, 5,7-dihydrobenzo[b][1,5]oxazonine-6(2H)-carboxylate and 2,5,6,7-tetrahydrobenzo[b][1,5]oxazonine cores, albeit in poor yields. Rather surprisingly, the N-allyl-N-(2-(N-allyl-4-methylphenylsulfonamido)benzyl)-4-methylbenzenesulfonamide scaffold gave the desired ring-closed 1,6-ditosyl-2,5,6,7-tetrahydro-1H-benzo[b][1,5]diazonine in a high yield. Furthermore, when treated with the catalyst [RuClH(CO)(PPh₃)₃] the alkene isomerized into conjugation only with the benzylic NTs group and not with the phenyl NTs group to afford the 1,6-ditosyl-2,3,6,7-tetrahydro-1H-benzo[b][1,5]diazonine structure.

Full text of DOI:10.1016/j.tet.2017.06.039

Accepted Manuscript
Observations concerning the synthesis of heteroatom-containing 9-membered benzo-
fused rings by ring-closing metathesis
Blessing A. Aderibigbe, Ivan R. Green, Tanya Mabank, Mari Janse van Rensburg,
Garreth L. Morgans, Manuel A. Fernandes, Joseph P. Michael, Willem A.L. van
Otterlo
PII:
S0040-4020(17)30672-5
10.1016/j.tet.2017.06.039
TET 28804
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 April 2017
Revised Date: 8 June 2017
Accepted Date: 19 June 2017
Please cite this article as: Aderibigbe BA, Green IR, Mabank T, van Rensburg MJ, Morgans GL,
Fernandes MA, Michael JP, van Otterlo WAL, Observations concerning the synthesis of heteroatom-
containing 9-membered benzo-fused rings by ring-closing metathesis, Tetrahedron (2017), doi: 10.1016/
j.tet.2017.06.039.
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Observations concerning the synthesis of
heteroatom-containing 9-membered benzo-fused
rings by ring-closing metathesis
Leave this area blank for abstract info.
a,b
c
c
c
a
Blessing A. Aderibigbe, Ivan R. Green, Tanya Mabank, Mari Janse van Rensburg, Garreth L. Morgans, Manuel A.
a,d
a
a,c
Fernandes, Joseph P. Michael and Willem A.L. van Otterlo*
a
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits, 2050, Johannesburg, South Africa;
Department of Chemistry, University of Fort Hare, Alice Campus, Ring Road, Alice, 5700, Eastern Cape, South Africa. Department of Chemistry and
b
c
d
Polymer Sciences, Stellenbosch University, Stellenbosch, Matieland, 7602, Western Cape, South Africa, E-mail: wvo@sun.ac.za for X-ray
crystallography.

1
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Tetrahedron
journal homepage: www.elsevier.com
Observations concerning the synthesis of heteroatom-containing 9-
membered benzo-fused rings by ring-closing metathesis
a,b
c
c
c
Blessing A. Aderibigbe, Ivan R. Green, Tanya Mabank, Mari Janse van Rensburg, Garreth L.
a
a,d
a
a,c
Morgans, Manuel A. Fernandes, Joseph P. Michael and Willem A.L. van Otterlo*
a
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, PO Wits, 2050, Johannesburg, Gauteng, South Africa.
Department of Chemistry, University of Fort Hare, Alice Campus, Ring Road, Alice, 5700, Eastern Cape, South Africa.
Department of Chemistry and Polymer Sciences, Stellenbosch University, Stellenbosch, Matieland, 7602, Western Cape, South Africa, E-mail: wvo@sun.ac.za
X-ray crystallography.
b
c
d
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2
009 Elsevier Ltd. All rights reserved.
A set of benzo-fused dienes with a 1,9-relationship and containing a variety of nitrogen and
oxygen heteroatoms were readily synthesized. These dienes were then treated with the Grubbs
second generation catalyst with the aim of synthesizing the 9-membered benzannelated
heterocycles containing two heteroatoms (either O,O, NR,NR or O,NR where R = Ts or Boc).
As previously observed in the literature, many of the dienes did not give the expected ring-
closed product. However, a number of the desired products did form, namely with the 1,2-
Available online
Keywords:
Ring-closing metathesis
9
1
5
-Membered ring systems
,2-Dihydrobenzo[c][1,5]oxazonin-7(5H)-one
,7-Dihydrobenzo[b][1,5]oxazonine-6(2H)-
dihydrobenzo[c][1,5]oxazonin-7(5H)-one,
carboxylate and 2,5,6,7-tetrahydrobenzo[b][1,5]oxazonine cores, albeit in poor yields. Rather
surprisingly, the N-allyl-N-(2-(N-allyl-4-methylphenylsulfonamido)benzyl)-4-
5,7-dihydrobenzo[b][1,5]oxazonine-6(2H)-
carboxylate
2
2
,5,6,7-Tetrahydrobenzo[b][1,5]oxazonine
,5,6,7-Tetrahydro-1H-benzo[b][1,5]diazonine
methylbenzenesulfonamide scaffold gave the desired ring-closed 1,6-ditosyl-2,5,6,7-tetrahydro-
1H-benzo[b][1,5]diazonine in a high yield. Furthermore, when treated with the catalyst
Isomerization
Benzo-fused
3 3
[RuClH(CO)(PPh ) ] the alkene isomerized into conjugation only with the benzylic NTs group
and not with the phenyl NTs group to afford the 1,6-ditosyl-2,3,6,7-tetrahydro-1H-
benzo[b][1,5]diazonine structure.
1
. Introduction
It has been shown that 9-membered ring systems are important
compounds with rather interesting properties (these
characteristics include structural and conformational traits). In
In the last two decades, ring-closing metathesis (RCM) has
become an established synthetic process for the construction of
small (5- and 6), medium (7–9) and larger (>9)-membered ring-
systems. The use of this method has been expanded owing to
the compatibility of the process with heteroatoms in the newly
created ring systems viz., nitrogen, oxygen and sulfur. It should
also be noted here that RCM has seen much application in the
area of natural products with medium-sized ring systems.
16
addition, (hetero)aromatic ring-fused 9-membered rings represent
structural features that have been found in natural products, a
1-5
17,18
typical example being stemmadenine 2,
a representative
member of the azonino[5,4-b]indole family (Figure 1), albeit that
apart from the indole portion the ring is fully saturated.
6,7
8-10
The incorporation of two adjacent alkene side chains onto
semi-)rigid motifs has also been employed synthetically, often
(
resulting in the corresponding ring-closed products being formed
11
in good yields. Examples include the incorporation of aromatic
rings as part of the diene-containing system, thus resulting in
benzo-fused systems with additional rings of various ring-sizes.
In addition, benzo-fused systems possessing a variety of
heteroatoms have been constructed in this way. In terms of our
research group’s contribution to this area, the following efforts
towards medium-sized benzo-fused heteroatom-containing
systems (1, figure 1) have been synthesized by RCM, namely 7-
Figure 1: Unsaturated 9-membered benzo-fused rings systems
12-14
12,13,15
and 8-membered
benzo-fused ring systems.
From a cursory perusal of the literature, it became evident that
the synthesis of 9-membered benzo-fused ring systems - a

2
Tetrahedron
ACCEPTED MANUSCRIPT
generic example 1 shown in figure 1 - had previously been
achieved with RCM reactions, albeit with various degrees of
success.
benzo[b]azonine 3, biaryl 4,
benzo[b][1,5]oxathionine 5, and silyloxy-containing 6. In
terms of indole examples, with respect to compound 2,
11
Examples include20,21the benzoyl-protected 1H-
19
substituted 2,5-dihydro-7H-
22
23
24,25
substituted 7,10,11,12-tetrahydroazonino[3,2,1-hi]indole 7,
26
[
1,4]diazonino[1,2-a]indole 8,
substituted 6,7-dihydro-5H-
27
dibenzo [c,e]azonine 9 and the hepatitis C virus polymerase
28
enzyme (NS5B) inhibitor 10 (Figure 2) all make up members of
this set. It should be noted that generation of 9-membered benzo-
fused rings has also been attempted by way of an enyne
metathesis strategy, but that this general approach remains
29,30
challenging.
In summary, it is evident that the relative paucity
of examples of 9-membered rings synthesized by metathesis is
reflected in the challenges (including entropic and
conformational constraints) associated with the generation of
Scheme 1: Importance of functional groups in metathesis
leading to 9-membered ring systems
31-33
such large ring systems.
These reports of the challenges of forming 9-membered rings
by RCM have prompted us to disclose results emanating from
our laboratory towards the synthesis of benzo-fused systems
containing either oxygen or nitrogen and a combination of these
two elements in the 9-membered ring. This general approach is
illustrated in the general scheme shown below (scheme 2).
Scheme 2: Proposed approach to various benzo-fused 9-membered ring
systems
2
. Results and discussion
The initial part of the project involved the synthesis of a
number of varied diene substrates in which an aromatic ring
formed part of the backbone illustrated in Figure 3.
Figure 2: Examples of benzo- and indole-fused 9-membered rings
generated by metathetic approaches
In a recent interesting case, Baell and co-workers observed
that during the synthesis of peptidomimetic compounds, the
attempted ring-closure of benzamide 11 into the anticipated 12
Figure 3: Scaffolds containing an aryl ring and two oxygen atoms in the
diene side chains
34,35
did not occur at all (scheme 1).
convert compound 11 into urea 13 in order to effect cyclization to
4, presumably via intramolecular hydrogen bonding (as shown
in 13) which enhanced the proximity of the two alkene side
In fact, it was necessary to
Therefore, the syntheses commenced with the oxygen
containing compounds (17a-e). The simplest of these scaffolds
viz., 1-(allyloxy)-2-[(allyloxy)methyl]benzene 17a, was readily
generated from 2-(hydroxymethyl)phenol 18 as described in the
1
34,35
chains allowing for participation in the RCM process.
36
literature. For the synthesis of compounds with a greater degree
of steric hindrance at the benzylic position, scaffolds 17b-d
3
7
(
figure 3) were generated from 2-allyloxybenzaldehyde 19 and
35
ethyl 2-(allyloxy)benzoate 20 respectively, by making use of an
appropriate Grignard addition followed by the allylation of the
resultant benzylic alcohol (Scheme 3). Finally, mixed ether-ester
scaffold was generated viz., allyl 2-allyloxybenzoate 22, which
was synthesized directly from salicylic acid 21 as described in

3
38
the literature by Brown and Duong, to complete this set of
oxygen-containing dienes.
ACCEPTED MANUSCRIPT
variant in this manner. Of interest here is that the two-step
allylation protocol gave better yields of product than an initial
NaH-mediated diallylation of the N-tosyl protected starting
material, since the latter protocol resulted in the formation of
multiple products.
Scheme 3: Synthesis of di-oxygen-containing precursors
The first of the bis-alkene scaffolds involving a mixed set of
heteroatoms was synthesized as illustrated in Scheme 4, using 2-
aminobenzyl alcohol 23 as the starting material. Transformation
of the amine group of 23 into the tosylamide and Boc analogues
was followed in both cases by an allylation with allyl bromide
mediated by potassium carbonate to yield the mono-allylated
analogues 24 and 25 respectively, in reasonable yield (Scheme
In order to maintain as close a structural similarity as possible
for this set of scaffolds, the corresponding benzylic oxidized
version
of
26
viz.,
allyl
2-[(N-allyl-4-
methylphenyl)sulfonamide]benzoate 28, was also synthesized
from anthranilic acid 27 via the known N-tosylanthranilic acid
4
). Failure of the benzylic hydroxyl group to undergo allylation
39
(Scheme 4).
under these conditions necessitated initial deprotonation with a
stronger base, viz., sodium hydride, prior to reaction with allyl
bromide.
A second, yet complementary, scaffold containing nitrogen
and oxygen atoms, but in different relative positions, were
next synthesized (compounds 33 and 34, Scheme 5). These
compounds had the oxygen atom directly linked to the aryl
ring and were synthesized from salicylaldehyde 29. The initial
allylation of the phenol group in 2-hydroxybenzaldehyde 29
was achieved in 90% yield and was followed by reductive
amination with allylamine and sodium triacetoxyborohydride
to give a high yield of the bis-allyl compound 30. Attempts to
convert this material into the Boc-protected analogue 33 or the
corresponding tosyl-protected analogue 34, under a variety of
conditions, was unsuccessful in our hands (numerous products
by tlc) and thus an alternative one-pot route was developed. In
this sequence of reactions, reductive amination of
salicylaldehyde 29 was achieved by firstly treating it with allyl
amine in the presence of crushed 4 Å molecular sieves. This
was followed by reduction of the intermediate imine with
sodium borohydride and subsequent reaction of the amine
with di-tert-butyl dicarbonate to afford the urethane 31 in 72%
yield, while tosylation gave the corresponding tosyl-protected
analogue 32 in a similar yield. Finally, a regular phenolic
allylation protocol gave the desired bis-allylation products 33
and 34 in yields of 86% and 43% respectively. It should be
mentioned that it was not necessary to synthesize the related
benzamide 11 as Baell and co-workers demonstrated that this
34,35
compound fails to undergo RCM.
Scheme 4: Scaffolds with nitrogen directly attached to the aryl ring
This afforded the desired di-allyl tosyl-protected compound
2
6. Unfortunately, we were unable to obtain the Boc-protected

4
Tetrahedron
ACCEPTED MANUSCRIPT
Figure 4: Scaffolds for which the RCM reactions were unsuccessful
under the following conditions: Grubbs second generation catalyst, CH Cl
2
2
,
o
o
3
0-35 C or toluene, 80 C.
Scheme 5: Scaffolds with oxygen directly attached to aryl ring
The first attempted metathesis cyclizations for the dioxygen-
containing dienes 17a-d were unfortunately very disappointing
Finally, molecules incorporating two nitrogen atoms in the
allylic side chains were generated from 2-aminobenzylamine 35
Scheme 6). Thus, global tosylation of 35 with tosyl chloride in
(See Figure 4 for structures that were not successfully ring-
(
closed). Initial attempts using the Grubbs second generation
40
pyridine gave a 59% yield of compound 36. Similarly,
42
41
catalyst at moderate temperature (reflux, CH Cl ) showed that
2 2
conversion of 35 into the di-Boc analogue 37 was achieved with
the starting material was not being consumed (tlc). Subsequent
reactions were performed under much more vigorous conditions,
in which the same catalyst was used in toluene and the reaction
Boc O in acetonitrile in 76% yield. Allylation of 36 then
2
proceeded smoothly to afford the diallyl substrate 38 in 83%
yield. However, the synthesis of the corresponding di-Boc
derivative proved to be too variable in our hands with most
products being typified by loss of the Boc group(s). Finally,
allylation of the diamine 35 gave the N-differentiated diallyl
analogue 39 in an expected low yield of 8% (Scheme 6).
o
temperature increased from ambient to 80 C. To ensure that the
products were not co-eluting with the starting dienes on the TLC
plates, column chromatography was performed on all the reaction
residues. However, isolation of the same starting materials 17a-d
in each case, as substantiated by NMR spectroscopy, confirmed
that cyclization had not occurred. In addition, and of notable
interest, was the absence of isomerized by-products, which were
identified later in other RCM reactions done in the study (vide
infra). It should also be noted that, as concentration has been
43
shown to affect RCM outcomes, the reaction concentrations
were kept well below 0.5 M (see experimental section for exact
concentrations). In a subsequent attempt to understand whether
steric issues might be involved in preventing the RCM process, a
single crystal X-ray structure was solved for 17d, which showed
that at least in the solid state, the allyl groups were essentially
kept far apart by a “triphenylalkoxy barrier” (see experimental
section for the ORTEP diagram of 17d and its precursor, [2-
(allyloxy)phenyl](diphenyl)methanol, a compound in which the
allyloxy and alcohol functionalities appear much closer together).
Based on our experiences with the synthesis of 8-membered
1
2,13,15,44
benzo-fused heterocycles by way of RCM reactions,
Scheme 6: Scaffolds with two nitrogen atoms
which for the most part provided product in high yields, it would
seem that the additional flexibility imparted to the 1,9-diene
system by the addition of one extra skeletal atom is a serious
enough limiting factor to disfavour the desired reaction. It can be
postulated too that the high coordinating abilities of the diallyl
ethers could be playing an additional important role in shutting
down the metathesis process.
With the eleven scaffolds in hand, a variety of RCM conditions
were applied to facilitate ring-closure. These are discussed in the
following section with successes summarized in Table 1.
Attempts at cyclizing the allyl 2-(but-3-en-1-yloxy)benzoate 22,
which is essentially an ester version of the Baell benzamide
34,35
1
1
shown in Scheme 1, were equally unsuccessful (figure 4),
confirming earlier observations concerning the challenges
associated with making 9-membered rings from these types of
systems by RCM.
The RCM results for the mixed N,O-containing dienes proved
to be more promising. Although attempted RCM of substrate 26

5
was unsuccessful, RCM of the ester 28 gave pr
A
od
C
uc
C
t 4
E
0
P
in
T
a
E
po
D
or MAan
N
d
U
the
S
N
C
C
R
H
I
CH=CH signals of the starting material, at δ 4.50
P
T
2
1
5% yield after prolonged heating in toluene (Table 1, entry a),
and 3.83 respectively, were absent in product 44 and were
replaced by new signals typical of the isomerized diene systems.
Of particular note was the following: a dq for the OCH at δ 6.35
with J 8.4 and 1.8 Hz clearly indicated a cis double bond, as well
as a dq for the NCH at δ 6.65 with J 14.1 and 1.8 Hz
characterizing a trans double bond. As to the assignment of the
respective cis α-H being adjacent to either the N or O atom, this
was clarified by comparison with the H NMR spectrum of
isomer 45. In the latter spectrum, it was evident that only one of
the side chains had undergone isomerization since the methylene
along with 38% of recovered starting material 28. This result is
of some interest since the presence of a carbonyl group over a
methylene group essentially allows for some RCM to occur. Of
additional interest, RCM involving 33, in which the amine and
oxygen atoms had been interchanged and with the amine being
Boc-protected, also resulted in the formation of the 9-membered
cyclized product 41 being obtained. In this instance, a slightly
better yield of 28% was obtained for the product 41, although no
starting material was recovered (Table 1, entry b).
1
signal assigned to the NCH CH=CH was still present at δ 3.83,
2
RCM, when applied to the tosylamide 34, afforded the desired
ring closed product 42, again in a rather poor yield (13%), but
nevertheless did provide evidence that formation of such 9-
membered rings by RCM was indeed possible (Table 1, entry c).
This reaction proved to be quite interesting since apart from the
desired 9-membered ring compound 42, two additional products
were isolated during the purification of 42, in addition to
recovered starting material (24%). The products obtained, in
which the allyl chain(s) had been isomerized, were 44 (12%) and
but that the signal for the OCH at δ 4.50 had disappeared.
2
Importantly, the observed dq at δ 6.26 with J 7.5 and 1.5 Hz for
compound 45 was quite similar to that of 44 and was
consequently assigned to the α-H of the O to support the two
assigned structures for 44 and 45.
4
5 (23%) (figure 5). It should be noted here that the relationship
between metathesis and isomerization has previously been
4
5-47
explored and productively exploited.
It is interesting to note
1
that from the H NMR spectra it could be deduced that the
allyloxy side chain in both 44 and 45 had isomerized to the
Figure 5: Side products obtained in the RCM reaction of substrate 34
intuitively less likely cis isomer in both products. This was based
1
on the following analysis of the H NMR spectra: both the OCH
2
Table 1: Summary of successful RCM reactions
Entry
no.
a
Substrate
Conditions
Product A
Yield
Grubbs ll (5 mol%)
Toluene, 70 C, 18 h
O
15%
o
O
(
38% of 28
recovered)
N
Ts
40
b
c
Grubbs ll (5 mol%)
Toluene, 70 C, 12 h
Boc
28%
o
N
O
O
41
Grubbs ll (5 mol%)
Ts
13%
o
Toluene, 70 C, 72 h
N
(
24% of 34
recovered,
also 12% of
44 and 23%
42
of 45)
d
Ts
N
Grubbs ll (10 mol%)
DCM, 60 C, 18 h
Ts
96%
o
N
N
Ts
N
38
Ts
43

6
Tetrahedron
ACCEPTED MANUSCRIPT
Lastly, the RCM procedure was applied to the two diamine
3
. Conclusion
scaffolds synthesized, namely 38 and 39. To our satisfaction the
ring-closed product 43 was obtained in 96% yield from the diene
From the examples covered in this work, it has been
demonstrated that the RCM methodology can indeed be utilized
in the formation of several benzannelated bis-heteroatom-
containing 9-membered heterocyclic molecules, albeit mostly in
unsatisfactory yields. However, predicting which systems will
successfully ring-close is still far from being clearly understood.
It does appear that spatial pre-organization of the two allyl chains
is important, with the bis-tosyl sulfonamide system 38 giving
ring-closed product 42 in an excellent yield. In attempting to
identify some contributing factors from the small set of bis-
alkenes studied, the following was noted: under the conditions
used: (a) systems having aryl and benzylic O-allyl side chains did
not undergo the RCM in our hands to form the desired 9-
membered ring systems; (b) the “benzylic” carbonyl group plays
a role when comparing diene systems 26 and 28 (with the latter
ester providing some product); (c) the replacement of an aryl O-
by an NTs-allyl group generally improved the RCM outcome (for
instance, RCM of 22 versus 28); (d) replacement of a benzylic O-
by an NR-allyl improves RCM (compare the unsuccessful results
with substrates 17a-d to those with 33 (R=Boc) and 34 (R= Ts)),
and finally, (e) protected N-allyl groups at the aryl and benzylic
positions, particularly bearing tosyl groups provided an ideal
system for RCM reaction. Furthermore, these observations
support results from other groups (for instance Beall and co-
3
8, while perhaps unsurprisingly, diene 39 failed to cyclize due
to the high coordinating affinity of the two secondary amines. It
should be stressed that for scaffold 38 only moderate reaction
o
conditions (CH Cl , 60 C for 18h) were required (Table 1, entry
2
2
d). Fortunately, the product 43 proved to be a crystalline solid
which allowed for a single crystal X-ray spectroscopic analysis to
be performed and confirmed that the desired ring-closure had
indeed occurred (See figure 6a). It would thus appear that in this
specific case, the presence of the two bulky tosyl groups on the
allylamines results in a pre-organized conformation in which the
RCM reaction becomes an efficient process.
34,35
workers ) where it was found that the positioning of functional
groups and their spatial characteristics, such as an ability to be
involved in intra-molecular bonding interactions, had
a
significant influence on RCM reaction outcomes. It should
further be noted that in select cases, side-products were obtained
due to isomerization of the allyl groups. Finally, application of
the isomerization catalyst [RuClH(CO)(PPh ) ] allowed for the
successful isomerization of diazocine 43 into the single
regioisomer 46.
3
3
a)
b)
Figure 6: ORTEP diagrams of the X-ray crystal structures of compounds
a) 43, b) 46, with all thermal ellipsoids at 50% probability, indicating the
successful isomerization reaction (43 → 46).
4
. Experimental
1
13
With the crystalline 1,6-bis[(4ꞌ-methylphenyl)sulfonyl]-2,5,6,7-
tetrahydro-1H-1,6-benzodiazonine 43 in hand, internal alkene
isomerization was investigated with the ruthenium hydride
isomerization catalyst, [RuClH(CO)(PPh ) ], as illustrated in
H NMR and C NMR spectra were recorded on Bruker 300,
Bruker DRX 400, Varian Inova 400 or Varian Inova 300
spectrometers at the frequency indicated. Infra-red spectra were
recorded on Bruker IFS 25, Bruker Vector 22 or Thermo Nicolet
Nexus 470 fourier transform spectrometers. Mass spectra were
recorded on a Kratos MS 9/50, VG 70E MS or VG 70 SEQ mass
spectrometer or alternatively a Waters API Q-TOF Ultima, GCT
Premier or SYNAPT G2 mass spectrometer. Macherey-Nagel
kieselgel 60 (particle size 0.063-0.200 mm) was used for
conventional silica gel chromatography. All solvents used for
reactions and chromatography were distilled prior to use.
3
3
48-50
Scheme 7.
rather surprisingly a single regioisomeric product 46 in a yield of
7%. Careful flash silica gel column chromatography then
Isomerization was complete after 18 h (tlc) giving
9
afforded a clean sample of the crystalline isomer 46 on which a
single crystal X-ray analysis was successfully performed after
recrystallization (figure 6b). This allowed for the rigorous
identification of the regioisomer 46 as the internally isomerized
product, with the alkene now in conjugation with the benzyl,
rather than that with the phenyl sulfonamide. This result was
somewhat unexpected as in previous work involving internal
isomerizations in 8-membered benzo-fused systems, mixtures of
Reactions were performed under a blanket of inert gas (Ar or N
unless specified.
)
2
1
-(Allyloxy)-2-[(allyloxy)methyl]benzene
17a:
2-
51
(Hydroxymethyl)phenol 18 (2.00 g, 16.1 mmol) in DMF (20 mL)
was cooled to 0 °C and treated with NaH (60% in oil, 1.14 g,
regioisomers were obtained.
3
5.4 mmol) and stirred for 15 min. Allyl bromide (8.39 g, 64.4
mmol, 4.0 equiv.) was added and the reaction mixture was stirred
o
at 24 C for 17 h. H O (50 mL) was added and the crude product
2
was extracted with EtOAc (5×100 mL). The combined filtrates
were dried (MgSO ) and the solvent removed to give a residue
4
which was purified by column chromatography using EtOAc:
hexane (1:9) as eluent to afford the product 17a as a yellow oil
(
1.20 g, 60% yield). Spectral data compared well to that
Scheme 7: Isomerization of compound 43 into 46.
36 1
published in the literature. H NMR (300 MHz, CDCl ): δ(ppm)
3
=
4.08 (d, 2H, J 5.4 Hz, OCH ), 4.54 (d, 2H, J 5.1 Hz, OCH ),
2
2
4
.60 (s, 2H, ArCH ), 5.17–5.43 (m, 4H, 2×OCH CH=CH ), 5.91–
2
2
2

7
6
6
.10 (m, 2H, 2×OCH CH=CH ), 6.84 (d, 1H
A
, J
C
8
C
.1
E
H
P
z,
T
A
E
rH
D
), MA1H
N
,
U
J 4
S
.5
C
H
R
z,
I
O
P
H
T
), 4.42 (d, 2H, J 5.1 Hz, OCH
), 5.78–5.91 (m, 1H, OCH CH=CH
2
2
), 5.12–5.24 (m,
2
2
.95 (dd, [app. t], 1H, J =J 7.5 Hz, ArH), 7.22 (dd [app. t], 1H,
2H, OCH
2
CH=CH
2
2
), 5.99 (d,
1
2
1
3
J =J 8.1 Hz, ArH), 7.41 (d, 1H, J 7.5 Hz, ArH); C NMR (75
1H, J 2.0 Hz, PhCH), 6.77 (d, 1H, J 8.4 Hz, ArH), 6.86 (dd [app.
1
2
MHz, CDCl ): δ(ppm) = 66.8 (CH ), 68.7 (CH ), 71.4 (CH ),
t], 1H, J =J 7.5 Hz, ArH), 7.12–7.32 (m, 5H, 5×ArH), 7.31 (d,
3
2
2
2
1
2
1
1
11.4 (CH), 116.7 (CH ), 116.9 (CH ), 120.6 (CH), 127.1 (C),
13
2
2
2
H, J 7.2 Hz, 2
×
ArH); C NMR (75 MHz, CDCl ): δ(ppm) =
3
28.3 (CH), 128.7 (CH), 133.3 (CH), 134.9 (CH), 155.9 (C);
+
68.8 (CH ), 72.3 (CHOH), 112.0 (2
×
CH), 117.5 (CH ), 117.6
2
2
HRMS: M , calcd for C H O 204.1150, found 204.1079.
13
16
2
(
(
CH), 120.9 (CH), 126.4 (CH), 127.0 (CH), 127.8 (CH), 128.0
CH), 128.5 (CH), 132.8 (C), 132.9 (CH), 143.3 (C), 155.6 (C);
1
-(Allyloxy)-2-[1-(allyloxy)ethyl]benzene
17b:
Methyl
+
magnesium iodide was pre-formed by treating Mg turnings (0.11
HRMS; M , calcd for C H O 240.1150, found 240.1160.
16
16
2
g, 24 mmol) in Et O (30 mL) at 0 °C with methyl iodide (0.23
[2-(Allyloxy)phenyl](phenyl)methanol (0.41 g, 1.7 mmol) in
DMF (20 mL) was treated with NaH (60% in oil, 0.14 g, 3.4
mmol) and stirred for 25 min. Allyl bromide (0.29 mL, 0.41 g,
2
mL, 0.52 g, 3.7 mmol), followed by vigorous stirring until the
37
turnings had all dissolved. 2-(Allyloxy)benzaldehyde 19 (0.50
g, 3.1 mmol) was then added drop-wise to the solution and the
2.0 mmol) was then added and the reaction mixture was stirred at
o
o
reaction mixture was stirred at 24 C for a further 18 h after
24 C for 18 h after which it was quenched with H O (50 mL)
2
which it was quenched with NH Cl (sat.) (20 mL), extracted
4
and the aqueous solution was extracted with EtOAc (4×100 mL)
using EtOAc (3×100 mL) and after drying the solvent (MgSO ) it
to afford
a
residue which was purified by column
4
was removed under vacuum and the residue purified by column
chromatography using EtOAc:hexane (1:9) as eluent to afford the
product 1-[2-(allyloxy)phenyl]ethanol as a colourless oil (0.42 g,
chromatography using EtOAc:hexane (1:9) as eluent to give the
product 17c as a colourless oil (0.45 g, 86% yield). H NMR (300
1
MHz, CDCl ): δ(ppm) = 3.94 (d, 2H, J 4.2 Hz, OCH ), 4.43 (s,
3
2
7
7% yield). This reaction was repeated and afforded product in
2
H, OCH ), 5.07–5.30 (m, 4H, 2×OCH CH=CH ), 5.82 (s, 1H,
2 2 2
1
similar yields. H NMR (300 MHz, CDCl ): δ(ppm) = 1.52 (d,
3
PhCHO), 5.88–5.91 (m, 2H, 2×OCH CH=CH ), 6.74 (d, 1H, J
2 2
3
H, J 6.5 Hz, CH ), 2.66 (bs, 1H, OH), 4.59 (dd, 2H, J 3.6, 1.5
3
8.1 Hz, ArH), 6.89 (dd [app. t], 1H, J =J 7.2 Hz, ArH), 7.08–
1 2
Hz, OCH ), 5.14 (m, 1H, CH CHOH), 5.30 (d, 1H, J 10.5 Hz, cis
2
3
7.22 (m, 4H, 4×ArH), 7.23 (br d, 2H, J 7.1 Hz, 2×ArH), 7.46 (dd,
OCH CH=CH ), 5.42 (d, 1H, J 17.3 Hz, trans OCH CH=CH ),
13
2
2
2
2
1
6
1
H, J 6.6, 1.2 Hz, ArH); C NMR (75 MHz, CDCl ): δ(ppm) =
3
6
6
7
6
1
.00–6.12 (m, 1H, OCH CH=CH ), 6.86 (d, 1H, J 8.2 Hz, ArH),
2 2
8.8 (OCH ), 69.8 (OCH ), 76.2 (CH), 111.7 (CH ), 116.5 (CH ),
17.2 (CH), 120.9 (CH), 127.0 (2×CH), 127.1 (2×CH), 128.1
2
2
2
2
.94–6.99 (m, 1H, ArH), 7.19–7.26 (m, 1H, ArH), 7.36 (d, 1H, J
13
.4 Hz, ArH); C NMR (75 MHz, CDCl ): δ(ppm) = 22.8 (CH ),
3
3
(
2×CH), 128.2 (CH), 131.1 (C), 133.1 (CH), 135.0 (CH), 142.1
6.5 (CH ), 68.7 (CHOH), 111.6 (CH), 117.5 (CH ), 120.9 (CH),
+
2
2
(C), 155.5 (C); HRMS; M , calcd for C H O 280.1463, found
19
20
2
26.1 (CH), 128.1 (CH), 132.9 (CH), 133.7 (C), 155.4 (C);
2
80.1458.
+
HRMS; M , calcd for C H O 240.1150, found 240.1160.
11
14
2
38
1
-[2-(Allyloxy)phenyl]ethanol (0.62 g, 3.5 mmol) in DMF (30
Ethyl 2-(allyloxy)benzoate 20: To a solution of ethyl 2-
mL) was treated with NaH (60% in oil, 280 mg, 6.99 mmol) and
hydroxybenzoate (1.3 g, 7.8 mmol) in acetone (50 mL) and
K CO (3.33 g, 24.1 mmol) was added allyl bromide (2.1 mL, 2.9
g, 24.0 mmol). The reaction mixture was stirred under reflux for
o
stirred at 24 C for 25 min. Allyl bromide (0.61 mL, 7.0 mmol)
2
3
o
was added and the reaction mixture was stirred at 24 C for 18 h.
H O (50 mL) was then added and the crude product was
2
18 h after which H O (50 mL) was added and the crude product
2
extracted with EtOAc (3×100 mL) which produced a residue
extracted with EtOAc (4×100 mL). The residue produced was
which was purified by column chromatography using
purified by column chromatography using EtOAc:hexane (5:95)
EtOAc:hexane (1:9) as eluent to afford the desired product 17b
as eluent to afford the product 20 as a colourless oil (1.54 g, 96%
1
1
as a yellow oil (0.65 g, 81% yield). H NMR (300 MHz, CDCl ):
yield). H NMR (300 MHz, CDCl
3
): δ(ppm) = 1.38 (t, 3H, J 7.1
), 4.36 (q, 2H, J 7.1 Hz, OCH CH ), 4.61 (s, 2H,
CH), 5.29 (d, 1H, J 10.5 Hz, cis OCH CH=CH ), 5.51 (dd,
1H, J 17.4, 1.5 Hz, trans OCH CH=CH ), 6.01–6.07 (m, 1H,
OCH CH=CH ), 6.93–7.00 (m, 2H, 2×ArH), 7.43 (dd, 1H, J 1.0,
3
δ(ppm) = 1.42 (d, 3H, J 6.3 Hz, CH ), 3.84–3.92 (m, 2H, OCH ),
Hz, CH
OCH
3
2
3
3
2
4
5
2
.54 (d, 2H, J 4.8 Hz, OCH ), 4.96 (q, 1H, J 6.3 Hz, CHCH ),
2
2
2
2
3
.15 (dd, 1H, J 1.0, 10.5 Hz, cis OCH CH=CH ), 5.24–5.28 (m,
2
2
2
2
H, OCH CH=CH ), 5.40 (dd, 1H, J 1.5, 17.3 Hz, trans
2
2
2
2
13
OCH CH=CH ), 5.87–6.10 (m, 2H, 2×CH CH=CH ), 6.38 (d,
7.5 Hz, ArH), 7.79 (dd, 1H, J 1.5, 7.5, Hz, ArH); C NMR (75
MHz, CDCl ): δ (ppm) = 14.2 (CH ), 60.6 CH ), 69.3 (CH ),
113.5 (CH), 117.2 (CH ), 120.2 (CH), 120.9 (C), 131.4 (CH),
132.6 (CH), 133.0 (CH), 157.8 (C), 166.2 (C=O); HRMS; M ,
calcd for C12 206.0943, found 206.0942.
2
2
2
2
1
7
H, J 8.2 Hz, ArH), 6.98 (dd [app. t], 1H, J =J 7.5 Hz, ArH),
3
3
2
2
1
2
.20 (dd, 1H, J 1.5, 8.1 Hz, ArH), 7.45 (dd, 1H, J 1.5, 7.5 Hz,
2
13
+
ArH); C NMR (75 MHz, CDCl ): δ(ppm) = 22.6 (CH ), 68.6
3
3
(
OCH ), 69.5 (OCH ), 70.9 (CH), 111.5 (CH), 116.3 (CH ),
H O
14 3
2
2
2
1
1
2
16.9 (CH ), 120.9 (CH), 126.0 (CH), 127.8 (CH), 132.4 (CH),
2
+
1-(Allyloxy)-2-[(allyloxy)(diphenyl)methyl]benzene
17d:
33.3 (CH), 135.1 (C), 155.5 (C); HRMS; M , calcd for C H O
14
18
2
Magnesium turnings (0.27 g, 11 mmol) in THF (20 mL) at 0 °C
were treated with bromobenzene (3.43 g, 2.29 mL, 5.0 mmol)
and stirred until the turnings had dissolved to form the phenyl
magnesium bromide. Ethyl 2-(allyloxy)benzoate 20 (0.90 g, 4.4
18.1306, found 218.1306.
1
-(Allyloxy)-2-[(allyloxy)(phenyl)methyl]benzene 17c: Phenyl
magnesium bromide was pre-formed by treating Mg turnings
(
0.11 g, 24 mmol) in THF (30 mL) at 0 °C with bromobenzene
mmol) was then added dropwise to the solution which was stirred
o
(0.80 mL, 1.2 g, 7.4 mmol), followed by stirring until the
at 24 C for 18 h after which NH
4
Cl (sat.) solution (30 mL) was
37
magnesium dissolved. 2-(Allyloxy)benzaldehyde 19 (0.50 g,
.1 mmol) was then added drop-wise to the solution and the
added to quench the reaction. The crude product was extracted
with EtOAc (4×50 mL) and the residue purified by column
chromatography using EtOAc:hexane (5:95) as eluent to afford
the product [2-(allyloxy)phenyl](diphenyl)methanol as a white
3
o
resulting reaction mixture was stirred at 24 C for a further 18 h
after which it was quenched with NH Cl (sat.) (50 mL) and
extracted with EtOAc (3×100 mL) to afford a residue which was
4
1
solid (0.64 g, 44% yield); mp: 99–101 °C. H NMR (300 MHz,
purified by column chromatography using EtOAc:hexane (5:95)
CDCl ): δ(ppm) = 4.36 (d, 2H, J 5.0 Hz, OCH ), 5.00–5.09 (m,
3
2
as
allyloxy)phenyl](phenyl)methanol as a colourless oil (0.28 g,
8% yield). Repetition of this experiment provided product in
eluent,
to
provide
the
product
[2-
2H, OCH CH=CH ), 5.25 (s, 1H, OH), 5.51–5.63 (m, 1H,
OCH CH=CH ), 6.53 (d, 1H, J 6.6 Hz, ArH), 6.82 (dd [app. t],
2 2
2 2
(
3
1H, J =J 7.5 Hz, ArH), 6.93 (d, 1H, J 8.1 Hz, ArH), 7.26–7.32
1 2
1
13
similar yields. H NMR (300 MHz, CDCl ): δ(ppm) = 2.97 (d,
(m, 11H, 11×ArH); C NMR (75 MHz, CDCl ): δ(ppm) = 69.3
3
3

8
Tetrahedron
(
OCH ), 81.8 (C), 113.3 (CH), 117.1 (CH ), 120.6 (CH), 126.9
independent reflections, θ
25.996°, 244 refined parameters,
max
-3
2
2
ACCEPTED MANUSCRIPT
(2×CH), 127.6 (4×CH), 127.7 (4×CH), 128.8 (CH), 130.1 (CH),
maximum residual electron density 0.742 and -0.363 e.Å . R =
1
+
1
32.1 (2×C), 135.9 (C), 146.5 (CH), 156.3 (C); HRMS; M , calcd
0.0785, wR = 0.1931. Crystallographic data for the structure
2
for C H O 316.1463, found 316.1467.
have been deposited with the Cambridge Crystallographic Data
Centre as deposition No. CCDC-1530893.
22
20
2
X-ray
crystal
structure
details
of
[2-
(allyloxy)phenyl](diphenyl)methanol (as shown in figure 7):
crystallized from EtOAc-hexane, formula: C H O , M=316.38,
22
20
2
3
crystal size 0.30 × 0.28 × 0.18 mm , a = 12.2100(11) Å, b =
4.9811(18) Å, c = 9.4275(10) Å, β = 102.277(5)°, V = 1685.0(3)
1
3
3
-1
Å , ρ = 1.247 Mg/m , µ = 0.078 mm , F(000) = 672, Z = 4,
calc
monoclinic, space group P21/c, T = 173(2) K, 13292 reflections
collected, 4175 independent reflections, θmax 28.262°, 221 refined
parameters, maximum residual electron density 0.314 and -0.296
-
3
e.Å . R = 0.0482, wR = 0.1229. Crystallographic data for the
1
2
structure have been deposited with the Cambridge
Crystallographic Data Centre as deposition No. CCDC-1530895.
Figure 8: ORTEP diagrams of the X-ray crystal structure of compound 17d,
with all thermal ellipsoids at 50% probability.
38
Allyl 2-allyloxybenzoate 22 : To a solution of salicylic acid
1 (1.50 g, 10.0 mmol) in dry acetone (10 mL) was added
2
pulverised KOH (1.50 g, 22.0 mmol) and the mixture was stirred
o
at 25 C for 30 min. Removal of the solvent on a rotary
evaporator afforded the white di-potassium salt which was
dissolved in anhydrous DMF (15 mL) to which allyl bromide
(
4.0 mL, 45.6 mmol) and anhydrous K CO (6.60 g, 47.8 mmol)
2 3
was added and the reaction mixture stirred for 18 h. H O (50 mL)
2
was added and the product extracted with EtOAc (3×50 mL). The
combined extracts were dried (MgSO ) to afford the product as
4
Figure 7: ORTEP diagrams of the X-ray crystal structure of compound [2-
an oily residue purified by column chromatography using
EtOAc:hexane (5:95) as eluent to yield the diallylated product 22
as a colourless oil (2.28 g, 100% yield). Spectra compared well to
(allyloxy)phenyl](diphenyl)methanol, with all thermal ellipsoids at 50%
probability.
38 1
that published in the literature.
H NMR (300 MHz CDCl3):
To a solution of [2-(allyloxy)phenyl](diphenyl)methanol (0.32 g,
δ(ppm) = 4.65 (dd, 2H, J 5.1, 1.5 Hz, OCH ), 4.83 (dd, 2H, J 1.2,
2
0
0
.99 mmol) in DMF (20 mL) at 0 °C was added NaH (60% in oil,
.08 g, 2 mmol) and the resulting mixture stirred for 30 min.
5
.7, Hz, COOCH ), 5.27–5.56 (m, 4H, 2×CH=CH ), 5.99–6.15
2 2
(
m, 2H, 2×CH CH=CH ), 6.97–7.03 (m, 2H, 2×ArH), 7.43–7.49
2 2
13
Allyl bromide (0.17 mL, 2.0 mmol) was added to the mixture and
o
(m, 1H, ArH), 7.83–7.87 (m, 1H, ArH); C NMR (75 MHz,
stirring continued for 18 h at 24 C. H O (50 mL) was then added
2
CDCl ): δ(ppm) = 65.5 (COOCH ), 69.5 (OCH ), 113.6 (CH ),
3
2
2
2
and the crude product extracted with EtOAc (4×100 mL) to give
a residue which was purified by column chromatography using
EtOAc:hexane (5:95) as eluent to afford the product 17d as a
1
1
17.5 (CH), 118.1 (CH), 120.4 (CH ), 120.6 (C), 131.8 (CH),
2
32.3 (CH), 132.8 (CH), 133.4 (CH), 158.2 (C), 165.9 (C=O).
+
1
HRMS: M , calcd for C H O 218.0943, found 218.0945.
13
14
3
white solid (0.23 g, 63% yield); mp: 98–100 °C. H NMR (300
MHz, CDCl ): δ(ppm) = 3.55 (d, 2H, J 3.3 Hz, OCH ), 4.19 (d,
3
2
N-Allyl-N-[2-(hydroxymethyl)phenyl]-4ꞌ-
52
2
H, J 3.9 Hz, OCH ), 4.84 (dd, 1H, J 17.4, 2.2 Hz, trans
2
methylbenzenesulfonamide 24 : To a solution of TsCl (8.38 g,
44.7 mmol) in pyridine (25 mL) at 0 °C was added 2-
aminobenzyl alcohol 23 (2.50 g, 20.3 mmol) and the reaction
OCH CH=CH ), 4.96 (dd, 1H,
J
J
1.0, 10.5 Hz, cis
1.0, 10.5 Hz, cis
2
2
OCH CH=CH ), 5.14 (dd, 1H,
2
2
o
OCH CH=CH ), 5.36–5.51 (m, 2H, OCH CH=CH2 and
2
2
2
mixture was stirred at 24 C for 18 h. Removal of the solvent
OCH CH=CH ), 5.87–5.93 (m, 1H, OCH CH=CH ), 6.77 (d, 1H,
2
2
2
2
under high vacuum gave a residue which was purified by column
chromatography using EtOAc:hexane (1:1) as eluent to afford the
J 8.1 Hz, ArH), 7.00 (dd [app. t], 1H, J =J 7.5 Hz, ArH), 7.21–
1
2
7
.27 (m, 8H, 8×ArH), 7.50 (m, 3H, 3×ArH), 7.87 (d, 1H, J 6.9
product
N-[2-(hydroxymethyl)phenyl]-4ꞌ-
13
Hz, ArH); C NMR (75 MHz, CDCl ): δ(ppm) = 64.7 (OCH ),
3
2
methylbenzenesulfonamide as a white solid (1.53 g, 28% yield);
6
8.6 (OCH ), 85.2 (C), 113.3 (CH), 112.9 (CH), 115.1 (CH ),
2
2
mp: 142–145 °C. Spectral data of this compound compared well
53 1
1
16.6 (CH ), 120.7 (CH), 126.6 (4×CH), 127.2 (CH), 127.8
2
with that published in the literature.
H NMR (300 MHz,
CDCl ): δ(ppm) = 2.38 (s, 3H, CH ), 4.39 (s, 2H, ArCH ), 7.05–
(
(
3
CH), 128.5 (4
C), 142.7 (CH), 155.4 (C); HRMS; M , calcd for C H O
2
56.1776, found 356.1772.
×
CH), 128.6 (2×CH), 132.8 (C), 133.0 (C), 135.2
3
3
2
+
7.09 (m, 2H, 2×ArH), 7.20–7.28 (m, 3H, 3×ArH), 7.43 (d, 1H, J
8.0 Hz, ArH), 7.64 (d, 2H, J 7.9 Hz, 2×ArH), 7.88 (bs, 1H, OH);
25
24
13
C NMR (75 MHz, CDCl ): δ (ppm) = 21.5 (CH ), 63.9 (CH ),
3
3
2
X-ray crystal structure details of compound 17d (as shown in
figure 8): crystallized from EtOAc-hexane, formula: C H O , M
123.4 (CH), 125.3 (CH), 127.0 (2×CH), 129.0 (CH), 129.2 (CH),
25
24
2
129.6 (2×CH), 131.6 (C), 136.3 (C), 136.9 (C), 143.7 (C);
3
+
=
356.44, crystal size 0.42 × 0.22 × 0.08 mm , a = 8.4586(18) Å,
HRMS: M , calcd for C H NO S 277.0773, found 277.0765.
14
15
3
b = 9.223(2) Å, c = 13.746(3) Å, α = 77.615(16)°, β =
To
a
solution
of
N-[2-(hydroxymethyl)phenyl]-4ꞌ-
3
8
1.225(16)°, γ = 66.978(14)°, V = 961.2(4) Å , ρ
= 1.232
methylbenzenesulfonamide (1.0 g, 3.7 mmol) in acetone (45 mL)
was added K CO (2.19 g, 15.8 mmol), followed by allyl bromide
1.91 g, 15.8 mmol) and the reaction mixture was then heated
calc
3
-1
Mg/m , µ = 0.076 mm , F(000) = 380, Z = 2, triclinic, space
group P , T = 173(2) K, 7057 reflections collected, 3778
2
3
(
-
1

9
with vigorous stirring at 60 °C for 22 h. H O (2
AC
0
m
C
L)
E
w
P
as
T
a
E
dd
D
ed MA(1
N
:4)
(0.95 g, 78% yield). H NMR (300 MHz, CDCl
(s, 3H, CH ), 3.85 (bs, 1H, NCH
4.35 (bs, 1H, NCH ), 4.69–4.76 (m, 2H, ArCH
2H, NCH CH=CH ), 5.21 (d, 1H, J 10.5 Hz, cis-OCH
5.33 (dd, 1H, J 1.5, 17.2 Hz, trans-OCH CH=CH ), 5.67–5.80
(m, 1H, NCH CH=CH ), 5.91–6.04 (m, 1H, OCH CH=CH ),
6.54 (d, 1H, J 7.9 Hz, ArH), 7.12 (dd [app. t], 1H, J =J 7.5 Hz,
ArH), 7.26–7.34 (m, 3H, 3×ArH), 7.54 (d, 2H, J 8.2 Hz, 2×ArH),
U
as
S
e
C
lu
R
en
I
t,
P
t
T
o afford the desired product 26 as a brown oil
2
1
to the cooled reaction mixture and extraction with EtOAc (3×100
mL) produced a residue which was purified by column
chromatography using EtOAc:hexane (3:7) as eluent, to afford
the desired compound 24 as a brown oil (1.13 g, 97% yield).
Spectral data of this compound compared well with that
3
): δ (ppm) = 2.44
), 4.06 (d, 2H, J 5.5 Hz, OCH
), 4.95–5.01 (m,
CH=CH ),
),
3
2
2
2
2
2
2
2
2
2
2
52 1
published in the literature. H NMR (300 MHz, CDCl ): δ(ppm)
2.46 (s, 3H, CH ), 3.01–3.09 (m, 1H, NCH ), 3.70–3.76 (m,
H, NCH ), 4.50 (bd, 2H, J 10.0 Hz, ArCH ), 4.94–5.03 (m, 3H,
2
2
2
2
3
=
1
2
3
2
1
2
2
13
NCH CH=CH and OH), 5.64–5.78 (m, 1H, NCH CH=CH ),
7.61 (d, 1H, J 7.7 Hz); C NMR (75MHz, CDCl
21.5 (CH ), 54.7 (CH ), 68.1 (CH ), 71.5 (CH ), 116.8 (CH
119.5 (CH ), 127.4 (CH), 127.7 (CH), 128.0 (2×CH), 128.5
(CH), 128.8 (CH), 129.4 (2×CH), 132.2 (CH), 134.7 (CH), 135.4
3
): δ (ppm) =
2
2
2
2
6
.45 (d, 1H, J 7.8 Hz, ArH), 7.14 (dd [app. t], 1H, J =J 8.0 Hz,
ArH), 7.26–7.36 (m, 3H, 3×ArH), 7.54–7.60 (m, 3H, 3×ArH);
3
2
2
2
2
),
1
2
2
13
C NMR (75MHz, CDCl ): δ(ppm) = 21.5 (CH ), 55.0 (CH ),
1.1 (CH ), 119.1 (CH ), 127.5 (CH), 128.0 (2×CH), 128.2 (CH),
2 2
3
3
2
+
(
C), 136.8 (C), 140.4 (C), 143.5 (C); HRMS: M -Ts, calcd for
6
1
1
C H NO 202.1223, found 202.1232.
13 16
29.0 (CH), 129.5 (2×CH), 131.1 (CH), 131.8 (CH), 134.6 (C),
+
37.0 (C), 142.3 (C), 143.9 (C); HRMS; M , calcd for
Allyl 2-N-allyl-N-tosylbenzoate 28: To a mixture of N-
tosylanthranilic acid (1.0 g, 3.4 mmol) (synthesized from
anthranillic acid 27 in 95% yield, as per reference ) and
anhydrous K CO (2.38 g, 17.2 mmol) in anhydrous DMF (20
mL) was added allyl bromide (2.08 g, 17.2 mmol) and the
mixture vigorously stirred at 80 C (oil bath) for 8 h. H O (80
mL) was added to the cooled solution which was then extracted
with Et O (3×50 mL). The extracts were dried (MgSO ) to afford
an oily residue which was purified by column chromatography
C H NO S 317.1085, found 317.1098.
17
19
3
3
9
tert-Butyl allyl[2-(hydroxymethyl)phenyl]carbamate 25: 2-
Aminobenzyl alcohol 23 (0.80 g, 6.5 mmol) was dissolved in
THF (30 mL) and Boc O (4.5 mL, 19 mmol) was added. The
reaction was then stirred at room temperature for 20 h. H O (20
mL) was then added and the crude product was then extracted
with EtOAc (4 × 100 mL), which was dried with MgSO . Silica
gel column chromatography was then performed using
EtOAc:hexane (1:4) as solvent to afford the desired compound,
2
3
2
o
2
2
2
4
4
using EtOAc:hexane (3:7) as eluent to give the product 28 as a
1
colourless oil (1.01 g, 79% yield). H NMR (300 MHz CDCl ):
tert-butyl-2-(hydroxymethyl)phenylcarbamate as a yellow oil
3
1
δ(ppm) = 2.43 (s, 3H, ArCH ), 4.29 (d, 2H, J 7.2 Hz, NCH ),
(
1.15 g, 76% yield). H NMR (300 MHz, CDCl ): δ(ppm) = 1.50
3
2
3
4
5
6
7
.71 (d, 2H, J 6.0 Hz, OCH ), 5.00–5.08 (m, 2H, CH=CH ),
2
2
(
s, 9H, 3×CH ) 2.96 (bs, 1H, NH), 4.56 (s, 2H, ArCH ), 6.96
–
3
2
.29–5.45 (m, 2H, CH=CH ), 5.85–6.15 (m, 2H, 2×CH=CH ),
2
2
7
1
.01 (m, 1H, ArH), 7.10 (d, 1H, J 7.1 Hz, ArH), 7.24–7.26 (m,
.92–6.95 (m, 1H, ArH), 7.25 (d, 2H, J 8.4 Hz, 2×ArH), 7.38–
.45 (m, 2H, 2×ArH), 7.53 (d, 2H, J 8.4 Hz, 2×ArH), 7.88–7.91
(m, 1H, ArH); C NMR (75 MHz, CDCl ): δ(ppm) = 21.5
1
3
H, ArH), 7.70 (bs, 1H, OH), 7.82 (d, 1H, J 8.1 Hz, ArH);
C
13
NMR (75MHz, CDCl ): δ(ppm) = 28.2 (3×CH ), 63.8 (CH ),
3
3
2
3
8
1
0.3 (C-O), 121.0 (CH), 123.1 (CH), 128.7 (CH), 128.8 (CH),
29.1 (C), 137.7 (C), 153.4 (C=O); HRMS: M , calcd for
(
1
ArCH ), 54.6 (NCH ), 66.1 (OCH ), 118.7 (CH ), 119.0 (CH ),
3 2 2 2 2
+
27.6 (2×CH), 128.2 (C), 129.4 (2×CH), 130.9 (CH), 131.3
(CH), 131.9 (CH), 132.1 (CH), 132.7 (CH), 133.3 (CH), 136.7
C), 137.9 (C), 143.2 (C), 165.8 (C=O); HRMS: M , calcd for
C H NO 249.1364, found 249.1356.
12
17
3
+
(
tert-Butyl-2-(hydroxymethyl)phenylcarbamate (0.994 g, 4.26
C H NO S 371.1192, found 371.1188.
2
0
21
4
mmol) was dissolved in acetone (30 mL) and K CO (2.35 g,
2
3
2
-Allyloxy-N-allylbenzylamine 30: To a mixture of 2-
allyloxybenzaldehyde (1.0 g, 6.3 mmol) (synthesized from
salicylaldehyde 29 in 90% yield, as per reference ) and
anhydrous MgSO4 (2.50 g) in THF (15 mL) was added
allylamine (0.34 g, 0.6 mmol) and the resulting yellowish
solution stirred for 4 h at 24 C. (AcO) NaBH (2.0 g, 9.4 mmol)
was then added at once and the resulting mixture stirred for a
further 18 h at 24 C after which it was treated with HCl (5% v/v,
0 mL) and H O (30 mL). EtOAc extraction (3×20 mL) and
drying (MgSO ) afforded a residue which was purified by
column chromatography using EtOAc:hexane (1:9) as eluent, to
yield the product 30 as a mobile oil (1.04 g; 87% yield). H NMR
300 MHz CDCl ): δ(ppm) = 3.13 (d, 2H, J 6.1 Hz, NCH ), 3.71
s, 2H, ArCH N), 4.51 (d, 2H, J 5.9 Hz, OCH ), 5.12–5.43 (m,
H, CH=CH ), 5.80–6.07 (m, 2H, CH=CH ), 6.80 (d, 1H, J 7.6
2 2
1
7.1 mmol) was added, followed by allyl bromide (1.08 g, 1.46
mL, 8.93 mmol). The reaction was then stirred at 60 °C for 18 h.
H O (20 mL) was added and the crude product was extracted
with EtOAc (4 × 100 mL). The solvent was removed under a
vacuum and column chromatography was performed using 10%
EtOAc:hexane (1:9) as eluent to afford the desired compound 25
3
7
2
o
3
1
as a yellow oil (0.745 g, 67% yield). H NMR (300MHz, CDCl ):
3
o
δ(ppm) = 1.52 (s, 9H, 3×CH ), 3.99 (d, 2H, J 5.5 Hz, NCH ),
.56 (s, 2H, ArCH ), 5.24 (d, 1H, J 10.5 Hz, one of
3
2
2
2
4
2
4
NCH CH=CH ), 5.32 (d, 1H, J 17.2 Hz, one of NCH CH=CH ),
2
2
2
2
5
1
8
.87–6.00 (m, 1H, NCH CH=), 6.95–6.99 (m, 1H, ArH), 7.12 (d,
2
1
H, J 7.3 Hz, ArH), 7.28–7.33 (m, 1H, ArH), 7.80 (bs, 1H, OH),
.00 (d, 1H, J 8.1 Hz, ArH); C NMR (75MHz, CDCl ): δ(ppm)
13
(
(
4
3
2
3
2
2
=
1
1
28.3 (3×CH ), 70.4 (CH ), 71.0 (CH ), 80.0 (C-O), 117.7 CH ),
3 2 2 2
20.1 (CH), 122.4 (CH), 125.3 (C), 129.1 (CH), 129.3 (CH),
+
Hz, ArH), 6.94 (dd [app. t], 1H, J =J 7.5 Hz, ArH), 7.16 (dd
1 2
13
38.4 (CH), 138.8 (C), 152.9 (C=O); HRMS: M , calcd for
[
app. t], 1H, J =J 7.6 Hz, ArH), 7.57 (d, 1H, J 7.5 Hz, ArH); C
1 2
C H NO 263.1521, found 263.1507.
15
21
3
NMR (75 MHz, CDCl ): δ(ppm) = 51.9 (NCH Ar), 57.3 (NCH ),
3
2
2
6
1
1
1
9.0 (OCH ), 111.7 (CH), 116.9 (CH ), 117.2 (CH ), 120.8 (CH),
2
2
2
N-Allyl-N-{2-[(allyloxy)methyl]phenyl}-4ꞌ-
methylbenzenesulfonamide 26: To solution of 4ꞌ-
methylbenzenesulfonamide 24 (1.07 g, 3.38 mmol) in THF (40
mL) was added NaH (60% in oil, 0.10 g, 4.2 mmol) at 0 °C and
the mixture was stirred for 1 h. Allyl bromide (0.37 mL, 0.50 g,
27.5 (CH), 128.7 (C), 129.9 (CH), 133.8 (CH), 136.8 (CH),
a
+
56.9 (C); HRMS: M , calcd for C H NO 191.1311, found
12
17
91.1316.
Allyl-(2-hydroxybenzyl)-carbamic acid tert-butyl ester
54
4
2
.2 mmol) was added to the reaction mixture which was stirred at
3
1 : To a solution of salicylaldehyde 29 (1.50 g, 12.3 mmol) in
o
4 C for 18 h. H O (20 mL) was added to quench any excess
2
anhydrous EtOH (20 mL) was added allylamine (0.70 g, 12
mmol) and crushed 4A molecular sieves (5.0 g) and the yellow
solution was stirred at 24 C for 18 h after which the solution was
NaH and extraction with EtOAc (4×100 mL) gave a crude
product purified by column chromatography using EtOAc:hexane
o

1
0
Tetrahedron
12 MAN
filtered. To the yellow filtrate was added N
A
aB
C
H
C
(
E
0.
P
45
T
g
E
,
D
N
U
-a
S
lly
C
l-N
R
-
I
(2-(allyloxy)benzyl)-4-
P
T
4
mmol) and stirring was continued for a further 24 h. Boc O (0.27
g, 13 mmol) was then added and the mixture was stirred for a
further 8 h. Saturated aqueous NH Cl (20 mL) was added and the
methylbenzenesulfonamide 34: To a solution of the tosyl
phenol 32 (0.14 g, 0.45 mmol) in dry acetone (25 mL) containing
anhydrous K CO (0.31 g; 2.3 mmol) was added allyl bromide
2
4
2
3
solution was further diluted with H O (40 mL). The aqueous
solution was extracted with EtOAc (3×40 mL) and dried
(0.28 g, 2.3 mmol) and the resultant mixture was vigorously
stirred and heated under reflux for 24 h. The cooled mixture was
filtered and the residue obtained by evaporation of the solvent
was chromatographed using EtOAc:hexane (1:4) as eluent to
afford the diallyl product 34 (0.70 g, 43% yield). Further elution
gave unreacted starting tosyl phenol (0.070 g; 0.23 mmol). The
2
(
MgSO ) to afford a residue which was purified by column
4
chromatography using EtOAc:hexane (1:9) as eluent to give the
pure product 31 as an oil (2.34 g, 72% yield). The data compared
41 1
well with the literature. H NMR (300 MHz CDCl ): δ(ppm) =
3
1
1
.47 (s, 9H, 3×CH ), 3.79 (d, 2H, J 6.5 Hz, NCH ), 4.31 (s, 2H,
yield based on starting material consumed is thus 87%. H NMR
3
2
ArCH N), 5.10–5.21 (m, 2H, CH=CH ), 5.72–5.86 (m, 1H,
(300 MHz CDCl ): δ(ppm) = 2.45 (s, 3H, ArCH ), 3.81 (d, 2H, J
2
2
3
3
CH=CH ), 6.79 (dd [app. t], 1H, J =J 7.5 Hz, ArH), 6.95 (d, 1H,
6.3 Hz, NCH CH), 4.44 (s, 2H, ArCH N), 4.50 (d, 2H, J 5.1 Hz,
2
1
2
2
2
J 7.6 Hz, ArH), 7.04 (d, 1H, J 7.5 Hz, ArH), 7.21 (dd [app. t],
OCH CH), 5.01–5.08 (m, 2H, NCH CH=CH ), 5.28–5.40 (m,
2 2 2
13
1
2
H, J =J 7.6 Hz, ArH); C NMR (75 MHz, CDCl ): δ(ppm) =
2H, OCH CH=CH ), 5.54–5.58 (m, 1H, NCH CH=CH ), 5.96–
1
2
3
2 2 2 2
8.3 (3×CH ), 46.6 (ArCH N), 49.0 (NCH ), 81.7 (C), 117.2
6.02 (m, 1H, OCH CH=CH ), 6.81 (d, 1H, J 8.1 Hz, ArH), 6.95
2 2
3
2
2
(
CH), 117.5 (CH ), 119.2 (CH), 122.6 (C), 130.0 (CH), 131.4
(dd [app. t], 1H, J =J 8.1 Hz, ArH), 7.22 (dd [app. t], 1H, J =J
2
1
2
1
2
+
(CH), 132.9 (CH), 146.5 (C), 156.5 (C=O); HRMS: M , calcd for
8.1 Hz, ArH), 7.31 (d, 2H, J 8.4 Hz, 2×ArH), 7.39 (d, 1H, J 8.1
13
C H NO 263.1522, found 263.1527.
Hz, ArH), 7.72 (d, 2H, J 8.4 Hz, 2×ArH); C NMR (75 MHz,
CDCl3): δ(ppm) 21.5 (ArCH3), 45.1 (ArCH N), 50.5
15
21
3
=
2
N-allyl-N-(2-hydroxybenzyl)-4-methylbenzenesulfonamide
2: To a solution of salicylaldehyde 29 (1.50 g, 12.3 mmol) in
(
NCH CH), 68.8 (OCH ), 111.4 (CH), 117.4 (CH ), 118.7 (CH ),
2 2 2 2
3
1
1
20.8 (CH), 124.8 (C), 127.3 (2×CH), 128.6 (CH),129.5 (2×CH),
anhydrous EtOH (20 mL) was added allylamine (0.70 g, 12
mmol) and crushed 4A molecular sieves (5.0 g) and the yellow
solution was stirred at 24 C for 18 h after which the solution was
30.0 (CH), 132.8 (CH), 133.2 (CH), 137.7 (C), 143.0 (C),
+
o
156.3(C); HRMS: M +1, calcd for C20
H24NO
3
S 358.1477, found
3
58.1468.
filtered. To the yellow filtrate was added NaBH (0.45 g, 12
4
mmol) and stirring was continued for a further 24 h. The
4-Methyl-N-(2-{[(4ꞌ-
resulting mixture was poured into H O (200 mL), extracted with
EtOAc (4×40 mL) which was dried and evaporated to a thick oil.
This material was immediately taken up in DCM (50 mL) to
methylphenyl)sulfonyl]amino}benzyl)benzenesulfonamide
2
40
36 : To a mixture of TsCl (8.6 g, 45 mmol) in pyridine (25 mL)
at 0 °C was added 2-aminobenzylamine 35 (2.5 g, 21 mmol) and
o
which TsCl (2.58 g, 13.5 mmol), NEt (1.83 g, 18.1 mmol) and
the resulting reaction mixture stirred for 20 h at 24 C. Removal
3
o
DMAP (10 mg) were added. After stirring at 25 C for 72 h, the
of the solvent under vacuum yielded a residue which was purified
by column chromatography using EtOAc:hexane (1:1) as eluent
to afford the product 36 as a white solid (5.1 g, 59% yield); mp:
127–129 °C. Spectral data of this compound compared well with
solvent was removed and the residue purified by column
chromatography using EtOAc:hexane (1:4) as eluent to afford the
1
tosylamide 32 as a white solid (2.81 g; 72%). H NMR (300 MHz
40 1
CDCl ): δ(ppm) = 2.47 (s, 3H, ArCH ), 3.70 (br s, 1H,
that published in the literature. H NMR (300 MHz,CDCl ):
3
3
3
NCH CH=CH ), 3.83 (br s, 1H, NCH CH=CH ), 4.19 (s, 1H,
δ(ppm) = 2.39 (s, 3H, CH ), 2.44 (s, 3H, CH ), 3.81 (d, 2H, J 6.6
2
2
2
2
3
3
ArCH N), 4.30 (s, 1H, ArCH N), 5.08–5.12 (m, 2H, CH=CH ),
Hz, ArCH ), 5.10–5.14 (m, 2H, 2×NH), 7.08–7.33 (m, 6H,
2
2
2
2
5
.43–5.49 (m, 1H, CH=CH ), 6.84–6.86 (m, 1H, ArH), 6.96–6.98
6×ArH), 7.34 (d, 2H, J 8.2 Hz, 2×ArH), 7.56 (d, 2H, J 8.2Hz,
2
13
(m, 1H, ArH), 7.10–7.35 (m, 4H, 4×ArH), 7.55–7.80 (m, 2H,
2×ArH), 7.72 (d, 2H, J 8.2 Hz, 2×ArH); C NMR (75 MHz,
CDCl ): δ(ppm) = 21.5 (2×CH ), 43.9 (CH ), 125.8 (CH), 126.7
13
2
×ArH); C NMR (75 MHz, CDCl ): δ(ppm) = 21.6 (CH ), 44.9
3
3
3
3
2
(
ArCH N-rotamer), 47.2 (ArCH N-rotamer), 49.4 (NCH CH-
(CH), 127.1 (2×CH), 127.3 (2×CH), 129.2 (CH), 129.5 (2×CH),
129.8 (2×CH), 130.7 (CH), 130.9 (C), 134.9 (C), 136.0 (C),
136.2 (C), 143.8 (C), 143.8 (C); HRMS: M , calcd for
2
2
2
rotamer), 50.9 (NCH CH-rotamer), 117.3 (CH), 119.5 (CH),
1
2
+
19.9 (CH ), 122.2 (C), 127.2 (2×CH), 128.5 (2×CH), 129.8
2
(
CH), 130.0 (CH), 130.2 (CH), 143.4 (CH), 144.0(C), 155.9 (C);
C H N O S 430.1021, found 430.1023.
21
22
2
4 2
+
HRMS: M , calcd for C H NO S 318.1164, found 318.1165.
17
20
3
N-Allyl-N-{2-{ally[(4ꞌ-
methylphenyl)sulfonyl]amino}methyl)phenyl]-4-
methylbenzenesulfonamide 38: To
Allyl-(2-allyloxybenzyl)-carbamic acid tert-butyl ester 33:
To a mixture of phenol 31 (0.50 g, 1.9 mmol) in dry acetone (20
mL) and anhydrous K CO (1.31 g, 9.5 mmol) was added allyl
a
solution
of
benzenesulfonamide 36 (4.0 g, 8.8 mmol) in acetone (160 mL)
2
3
bromide (1.2 g, 9.5 mmol) and the mixture was vigorously stirred
under reflux for 18 h, cooled and filtered. The residue obtained
by evaporation of the solvent was purified by column
containing K CO (4.88 g, 35.4 mmol) was added allyl bromide
(4.83 g, 39.9 mmol) and the reaction mixture was vigorously
2
3
stirred for 18 h at 60 °C. H O (100 mL) was added and the crude
2
chromatography using EtOAc:hexane (1:9) as eluent to afford the
product was extracted with EtOAc (4×200 mL) to afford a
residue purified by column chromatography using EtOAc:hexane
1
product 33 as an oil (0.50 g, 86%). H NMR (300 MHz CDCl ):
3
δ(ppm) = 1.43 (s, 9H, 3×CH ), 3.77–3.89 (m, 2H, NCH ), 4.43–
(3:7) as eluent to give the product 38 as a white solid (3.8 g, 83%
3
2
1
4
.55 (m, 4H, ArCH N and OCH ), 5.09–5.42 (m, 4H, 2×
yield); mp: 117–119 °C. H NMR (300 MHz, CDCl ): δ (ppm) =
2
2
3
CH=CH ), 5.70–5.86 (m, 1H, NCH CH=CH ), 6.01–6.10 (m,
2.45 (s, 3H, CH ), 2.46 (s, 3H, CH ), 3.69–3.79 (m, 2H, ArCH ),
2
2
2
3
3
2
1
H, OCH CH=CH ), 6.84 (d, 1H, J 8.4 Hz, ArH), 6.93 (dd [app.
3.89 (dd, 1H, J 6.2, 15.2 Hz, NCH ), 4.39 (dd, 1H, J 6.2, 15.6 Hz,
2
2
2
13
t], 1H, J =J 8.2 Hz, ArH), 7.18–7.20 (m, 2H, 2×ArH); C NMR
NCH ), 4.51 (d, 1H, J 17.0 Hz, NCH ), 4.76 (d, 1H, J 17.0 Hz,
1
2
2
2
(
75 MHz, CDCl ): δ(ppm) = 28.4 (3×CH ), 44.6 (ArCH N), 49.2
NCH ), 4.94–5.07 (m, 4H, 2×NCH CH=CH ), 5.52–5.73 (m, 2H,
3
3
2
2
2
2
(
NCH ), 68.8 (OCH ), 79.8 (C), 111.4 (CH), 116.4 (C), 117.2
2×NCH CH=CH ), 6.41 (d, 1H, J 7.9 Hz, ArH), 7.09 (dd [app. t],
2 2
2
2
(
CH ), 118.6 (CH ), 120.6 (C), 128.0 (2×CH), 133.3 (CH), 134.0
1H, J =J 7.6 Hz, ArH), 7.34–7.36 (m, 5H, 5×ArH), 7.50 (d, 2H,
2
2
1 2
+
(CH), 155.9 (2×C); HRMS: M , calcd for C H NO 303.1836,
J 7.7 Hz, 2×ArH), 7.74 (d, 1H, J 7.8 Hz, ArH), 7.77 (d, 2H, J 7.7
13
18
25
3
found 303.1830.
Hz, 2×ArH); C NMR (75 MHz, CDCl ): δ (ppm) = 21.5
3
(
2×CH ), 47.5 (CH ), 51.2 (CH ), 54.8 (CH ), 118.8 (CH ), 119.9
3 2 2 2 2
(
CH ), 127.2 (4×CH), 128.1 (2×CH), 128.5 (CH), 128.8 (CH),
2

1
1
1
(
29.4 (2×CH), 129.7 (2×CH), 132.0 (CH), 1
C), 137.1 (2×C), 138.9 (C), 143.2 (C), 143.8 (C); HRMS; M ,
calcd for C H N O S 511.1647, found 511.1680.
A
32
C
.5
C
(C
E
H
P
),
T
1
E
34
D
.6 MAN
1
U
-To
S
s
C
yl-
R
2,
I
5-dihydrobenzo[c][1,5]oxazonin-7(1H)-one
P
T
+
40: Diene 28 (0.21 g, 0.60 mmol) in dry toluene (25 mL) was
treated with Grubbs II catalyst (5 mol%, 0.02 g, 0.03 mmol) and
the reaction mixture stirred for 18 h at 70 C. Removal of the
solvent afforded a residue which was purified by careful column
chromatography using EtOAc:hexane (5-40% gradient) as eluent
to give starting material 28 (0.080 g, 38% recovered), followed
by the cyclized product 40 as a thick oil (0.050 g, 15%). H NMR
300 MHz CDCl ): δ(ppm) = 2.40 (s, 3H, ArCH ), 4.18–4.43 (m,
H, NCH ), 4.68–4.75 (m, 1H, OCH ), 5.02–5.05 (m, 1H,
2 2
OCH ), 5.80–6.07 (m, 2H, CH=CH), 6.88–6.92 (m, 1H, ArH),
.27 (d, 2H, J 8.2 Hz, 2×ArH), 7.29–7.40 (m, 2H, 2×ArH), 7.52
(d, 2H, J 8.2 Hz, 2×ArH), 7.70–7.86 (m, 1H, ArH); C NMR (75
MHz, CDCl ): δ(ppm) = 21.5 (CH ), 53.4 and 54.6 (NCH ), 64.8
and 66.1 (OCH ), 105.0 (C), 118.8 (CH), 119.0 (CH), 127.5
CH), 127.6 (CH), 128.3 (CH), 128.4 (CH), 129.4 (2×CH), 130.9
CH), 132.6 (CH), 137.9 (2×C), 143.2 (C), 165.6 (C); HRMS;
27
30
2
4 2
o
N-Allyl-2-(allylamino)methyl)aniline 39: To a mixture of 2-
aminobenzylamine 35 (0.37 g, 3.1 mmol) in anhydrous acetone
(20 mL) and potassium carbonate (0.97 g, 7.0 mmol), was added
allyl bromide (0.73 g, 6.0 mmol) and the resulting mixture was
vigorously stirred under reflux for 4 h. The cooled solution was
filtered and evaporation of the solvent afforded a residue which
was purified by very careful silica gel column chromatography
using EtOAc/hexane (1:4) as eluent, to afford a mixture of
products, followed by the desired diallyl compound 39 as a
mobile oil (0.050 g, 8% yield). H NMR (300 MHz CDCl ):
δ(ppm) = 3.05 (s, 2H, NCH CH=), 3.06 (s, 2H, NCH CH=), 3.58
1
(
2
3
3
2
7
13
1
3
3
3
2
2
2
2
(s, 2H, ArCH N), 4.50–4.80 (broad signal, 2H, 2×NH), 5.14–5.18
2
(
(m, 4H, 2× =CH ), 5.83–5.90 (m, 2H, 2×=CH), 6.63–6.65 (m,
2
(
2
H, 2×ArH), 6.97 (d, 1H, J 8.2 Hz, H-5), 7.07 (dd [app. t], 1H,
+
13
M , calcd for C18
H17NO
3
343.0879, found 343.0871.
J =J 8.3 Hz, ArH); C NMR (75 MHz, CDCl ): δ(ppm) = 56.1
1
2
3
(
2× NCH CH=), 57.4 (ArCH N), 115.5 (CH), 117.6 (CH), 118.0
Tert-butyl
2,5-dihydrobenzo[b][1,5]oxazonine-6(7H)-
2
2
(
2×=CH ), 122.8 (C), 128.2 (CH), 130.6 (CH), 135.1 (2×=CH),
carboxylate 41: Diene 33 (0.34 g, 1.1 mmol) in dry toluene (40
2
1
47.1 (C); HRMS calcd for C H N 202.1471, found 202.1468.
mL) was treated with Grubbs II catalyst (5 mol %, 0.05 g, 0.06
mmol) and the reaction mixture stirred for 12 h at 70 C.
Removal of the solvent afforded a residue which was purified by
careful column chromatography using EtOAc:hexane (5:95) as
eluent to give the desired cyclized product 41 as a thick oil
13
18
2
o
Unsuccessful RCM reactions:
As initial RCM experiments with the Grubbs II catalyst (5–10
mol%) in CH Cl2 only returned unreacted starting material,
subsequent reactions were performed in dry toluene (0.3–0.7 M)
at 80 C, for a minimum of 18 h. Reactions were monitored by
TLC and removal of the solvent afforded residues which were
purified by careful column chromatography using EtOAc:hexane
mixtures as eluent to give compounds which were evaluated by
NMR spectroscopy. Some of the unsuccessful reaction conditions
are described in the table 2 below:
2
1
(0.090 g, 28% yield). H NMR (300 MHz CDCl
): δ(ppm) = 1.51
CH=CH), 4.46–4.54 (m,
N), 4.80–4.90 (m, 2H, CH=CH), 6.84 (d,
1H, J 8.1 Hz, ArH), 6.95 (dd [app. t], 1H, J =J 8.4 Hz, ArH),
7.20–7.25 (m, 2H, 2×ArH); C NMR (75 MHz, CDCl ): δ(ppm)
= 28.6 (3×CH ), 41.2 and 41.8 (NCH CH=), 46.1 and 46.8
(ArCH N), 68.4 and 68.5 (OCH ), 79.8 and 80.2 (C), 111.4
2×CH), 121.2 (C), 126.8 (CH), 128.6 (CH), 130.0 (CH), 130.7
3
o
(s, 9H, 3×CH
4H, OCH and ArCH
2
), 3.69–3.78 (m, 2H, NCH
3
2
2
1
2
13
3
3
2
2
2
(
(
Table 2:
+
CH), 156.0 (C), 156.8 (C); HRMS; M , calcd for
C H NO 275.1522, found 275.1523.
Starting material
Reaction
Outcome
16 21
3
concentration (M),
toluene
6
-Tosyl-2,5,6,7-tetrahydrobenzo[b][1,5]oxazonine 42: To a
solution of the O-allyl-N-allyl tosylamide 34 (0.11 g, 0.31 mmol)
in dry toluene was added Grubbs II catalyst (0.01 g, 0.01 mmol)
and the mixture was heated at 70 C with stirring for 72 h. The
1
7a
0.033
Starting material
o
recovered
(30%)
residue obtained upon removal of the solvent was
chromatographed and eluted with EtOAc:hexane (1:4) to afford a
thick colourless oil (0.05 g) comprising a mixture of compounds.
PLC of this mixture with the same solvent to give 4 major bands:
and decomposition
observed
1
1
1
2
7b
7c
7d
2
0.068
0.036
0.042
0.070
Starting material
recovered (30%)
Band 1: A white semi-crystalline solid of the diconjugated
isomerized material, 4-methyl-N-[(E)-prop-1-en-1-yl)-N-(2-
Starting material
recovered (44%)
{[(Z)-prop-1-en-1-yl]oxy}benzyl)benzenesulfonamide
44
1
(
0.060 g, 12% yield). H NMR (300 MHz CDCl ): δ(ppm) = 1.58
3
Decomposition
observed
(
dd, 3H, J 1.8, 6.9 Hz, CH=CHCH ), 1.69 (dd, 3H, J 1.8, 6.9 Hz,
3
CH=CHCH ), 2.46 (s, 3H, ArCH ), 4.54 (s, 1H, ArCH N
3
3
2
Only
material observed
by NMR
spectroscopy
starting
rotamer), 4.59 (s, 1H, ArCH
2
N rotamer), 4.73–4.80 (m, 1H,
CH=CHCH ), 4.91–4.95 (m, 1H, CH=CHCH ), 6.35 (dq, 1H, J
3 3
(
1.8, 8.4 Hz, cis OCH=CH), 6.65 (dq, 1H, J 1.8, 14.1 Hz, trans
NCH=CH), 6.91 (d, 1H, J 7.5 Hz, ArH), 7.03 (dd [app. t], 1H,
J =J 7.5 Hz, ArH), 7.22 (dd [app. t], 1H, J =J 7.5 Hz, ArH),
1
2
1
2
2
3
6
9
0.035
0.033
Decomposition
observed
7
.33 (d, 2H, J 8.1 Hz, 2×ArH), 7.40 (d, 1H, J 7.5 Hz, ArH), 7.73
13
(d, 2H, J 8.1 Hz, 2×ArH); C NMR (75 MHz, CDCl ): δ(ppm) =
3
1
5.3 (2×CH ), 21.6 (ArCH ), 44.0 (ArCH N), 107.6 (CH), 114.1
3 3 2
Only
starting
(CH), 122.8 (CH), 124.7 (CH), 126.3 (C), 128.0 (2×CH), 128.2
material observed
(
CH), 128.3 (CH), 128.3 (2×CH), 136.3 (C), 141.9 (C); HRMS;
(by
NMR
+
M +1, calcd for C H NO S 358.1477, found 358.1466.
spectroscopy
20 24
3
Band 2: Thick oil (0.015 g, 23% yield) for the cis-O-
propenyltosylamide, (Z)-N-allyl-4-methyl-N-(2-(prop-1-en-1-
yloxy)benzyl)benzenesulfonamide 45. H NMR (300 MHz
1
Successful RCM reactions:
CDCl ): δ(ppm) = 1.67 (dd, 3H, J 1.5, 6.9 Hz, CH=CHCH ), 2.45
3
3

1
2
Tetrahedron
(
s, 3H, ArCH ), 3.83 (sharp m, 2H, NCH
A
CH
C
=
C
CH
E
),
P
4
T
.42
E
D
(s, MAso
NU
lve
nt
S
w
C
as
R
re
I
moved under high vacuum and the residue purified
P
T
3
2
1
H, ArCH N rotamer), 4.47 (s, 1H, ArCH N rotamer), 4.85–4.95
by column chromatography using EtOAc:hexane (3:7) as eluent,
2
2
(
m, 1H, CH=CHCH ), 5.00–5.10 (m, 2H, CH=CH ), 5.50–5.63
to afford the product 46 as a brown-coloured solid (0.029 g, 97%
3
2
1
(m, 1H, NCH CH=CH), 6.26 (dq, 1H, J 1.5, 6.0 Hz, cis
yield); mp: 192–196 °C. H NMR (300 MHz, CDCl ): δ (ppm) =
2
3
OCH=CH), 6.88 (d, 1H, J 7.5 Hz, ArH), 7.05 (dd [app. t], 1H,
J =J 7.5 Hz, ArH), 7.22 (dd [app. t], 1H, J =J 7.5 Hz, ArH),
1.76–1.99 (m, 1H, NCH CH ), 2.04–2.17 (m, 1H, NCH CH ),
2
2
2
2
2.35 (s, 3H, CH ), 2.37 (s, 3H, CH ), 3.02-3.08 (m, 1H,
1
2
1
2
3
3
7
.31 (d, 2H, J 8.4 Hz, 2×ArH), 7.45 (d, 1H, J 7.5 Hz, ArH), 7.72
NCH CH ), 3.91–3.98 (m, 1H, NCH CH ), 4.46–4.59 (m, 2H,
2 2 2 2
13
(d, 2H, J 8.4 Hz, 2×ArH); C NMR (75 MHz, CDCl ): δ(ppm) =
ArCH ), 5.61–5.65 (m, 1H, NCH=CH), 6.09 (d, 1H, J 7.1 Hz,
3
2
9
1
1
.4 (=CHCH ), 21.5 (ArCH ), 44.7 (ArCH N), 50.5 (NCH CH=),
NCH=CH), 6.34 (d, 1H, J 7.8 Hz, ArH), 7.08–7.13 (m, 1H,
ArH), 7.19–7.23 (m, 4H, 4×ArH), 7.29–7.34 (m, 1H, ArH), 7.44
(d, 2H, J 7.9 Hz, 2×ArH), 7.62 (d, 2H, J 7.9 Hz, 2×ArH), 7.73 (d,
3
3
2
2
07.9 (CH), 114.4 (CH), 118.8 (CH ), 122.6 (CH), 122.7 (C),
2
27.0 (2×CH), 127.2 (CH), 128.7 (2×CH), 129.6 (CH), 132.6
13
(CH), 137.5 (C), 140.7 (CH), 143.1 (C), 155.3 (C); HRMS;
1H, J 7.6 Hz, ArH); C NMR (75 MHz, CDCl ): δ (ppm) = 21.5
3
+
M +1, calcd for C H NO S 358.1477, found 358.1467.
(CH ), 21.6 (CH ), 25.2 (CH ), 51.8 (CH ), 52.9 (CH ), 127.3
20
24
3
3
3
2
2
2
(
1
CH), 127.4 (2×CH), 127.6 (2×CH), 129.0 (CH), 129.3 (CH),
29.5 (2×CH), 129.6 (2×CH), 130.3 (CH), 132.0 (CH), 132.8
(CH), 135.4 (C), 136.0 (C), 137.9 (C), 140.1 (C), 143.6 (C),
Band 3: Starting material 34 (0.026 g, 24% recovered).
Band 4: White semisolid crystalline metathesis product, 6-
+
tosyl-2,5,6,7-tetrahydrobenzo[b][1,5]oxazonine 42 (0.060 g,
143.6 (C); HRMS; M , calcd for C25
482.1341.
H N O S 482.1334, found
26 2 4 2
1
1
3%). H NMR (300 MHz CDCl ): δ(ppm) = 2.46 (s, 3H,
3
ArCH ), 3.89 (d, 2H, J 8.4 Hz, NCH CH=CH), 4.37 (s, 2H,
3
2
X-ray crystal structure details of compound 46: crystallized
from EtOAc-hexane, formula: C H N O S , M = 482.60, crystal
ArCH N), 4.73 (dd, 2H, J 0.9, 5.7 Hz, OCH CH=CH), 5.56–5.82
2
2
25
26
2
4 2
(
7
m, 2H, CH=CH), 7.04 (dd [app. t], 2H, J =J 7.8 Hz, 2×ArH),
3
1
2
13
size 0.34 × 0.22 × 0.18 mm , a = 14.600(4) Å, b = 10.430(3) Å, c
3
.01–7.40 (m, 4H, 4×ArH), 7.74 (d, 2H, J 8.1 Hz, 2×ArH);
C
=
15.950(4) Å, b = 107.694(5)°, V = 2314.0(10) Å , ρ = 1.385
calc
3 -1
NMR (75 MHz, CDCl ): δ(ppm) = 21.5 (ArCH ), 46.1
3
3
Mg/m , µ = 0.266 mm , F(000) = 1016, Z = 4, monoclinic, space
group P21/c, T = 173(2) K, 13269 reflections collected, 4538
(
ArCH N), 47.9 (NCH CH), 68.3 (OCH ), 119.5 (CH), 123.9
2 2 2
(
1
CH), 127.1 (2×CH), 128.8 (C), 129.7 (2×CH), 129.8 (CH),
29.9 (CH), 131.4 (CH), 131.6 (CH), 137.7 (C), 143.2 (C), 157.9
independent reflections, θmax 25.999°, 300 refined parameters,
-3
+
maximum residual electron density 0.232 and -0.411 e.Å . R
1
=
(C); HRMS; M +1, calcd for C H NO S 330.1164, found
18 20 3
0
.0357, wR = 0.0903. Crystallographic data for the structure
2
3
30.1155.
,6-Bis[(4ꞌ-methylphenyl)sulfonyl]-2,5,6,7-tetrahydro-1H-
have been deposited with the Cambridge Crystallographic Data
Centre as deposition No. CCDC-1530896.
1
1
,6-benzodiazonine 43: Diene 38 (0.10 g, 0.19 mmol) in CH Cl2
2
5
. Acknowledgements
(10 mL) was treated with the Grubbs II catalyst (10 mol%, 0.017
g, 0.02 mmol) and the reaction mixture was stirred for 18 h under
reflux (60 °C, oil bath). Removal of the solvent under high
vacuum gave a residue which was purified by column
chromatography using EtOAc:hexane (1:4) as eluent to afford the
This work was supported by the National Research
Foundation (NRF), Pretoria (Grant CPRR14071475516), the
University of the Witwatersrand (University and Science Faculty
Research Councils) and Stellenbosch University (Faculty and
Departmental funding). We also gratefully acknowledge Mr R.
Mampa (University of the Witwatersrand) and Dr J. Brand and
Ms. E. Malherbe (Stellenbosch University) for the NMR
spectroscopy service. Finally, Mr T. van der Merwe (University
of the Witwatersrand), Dr A. Dinsmore and Mrs M. Ferreira
cyclized product 43 as a white solid (0.088 g, 96% yield); mp:
1
8
3
4–89 °C. H NMR (300 MHz, CDCl ): δ = 2.46 (s, 6H, 2×CH ),
3
3
.53–3.60 (m, 2H, ArCH ), 4.05–4.12 (m, 1H, NCH ), 4.29–4.34
2
2
(
m, 1H, NCH ), 4.56–4.65 (m, 2H, NCH ), 5.56–5.59 (m, 2H,
2
2
CH=CH), 6.47 (d, 1H, J 7.9 Hz, ArH), 7.15–7.19 (m, 1H, ArH),
7
2
2
1
.26–7.35 (m, 5H, 5×ArH), 7.55–7.61 (m, 3H, 3×ArH), 7.73 (bd,
(
University of the Witwatersrand, LRMS), Ms J. Schneider and
13
H, J 8.2 Hz, 2×ArH); C NMR (75 MHz, CDCl ): δ(ppm) =
3
Ms M. Ismail (Mass Spectroscopy Service, University of
Dortmund and Max Planck Institute for Molecular Physiology,
Dortmund, Germany and Mr B. Moolman, Mr F. Hiten and Dr
M. Stander (Central Analytical Facilities (CAF), Stellenbosch
University) are gratefully acknowledged for providing mass
spectroscopy services.
1.5 (CH ), 21.6 (CH ), 44.7 (CH ), 47.7 (CH ), 48.0 (CH ),
3
3
2
2
2
26.8 (2×CH), 126.9 (CH), 127.6 (CH), 127.9 (2×CH), 129.1
(CH), 129.4 (CH), 129.6 (2×CH), 129.8 (2×CH), 130.7 (CH),
1
32.4 (CH), 135.0 (C), 137.6 (C), 138.3 (C), 139.2 (C), 143.3
+
(C), 143.9 (C); M , calcd for C H N O S 482.1334, found
25 26 2 4 2
4
82.1338.
X-ray crystal structure details of compound 43: crystallized
6
. References
from EtOAc-hexane, formula: C H N O S , M = 482.60, crystal
2
5
26
2
4 2
3
size 0.22 × 0.16 × 0.03 mm , a = 14.554(7) Å, b = 10.454(5) Å, c
3
=
15.725(7) Å, b = 107.694(5)°, V = 2329.7(18) Å , ρ = 1.376
calc
3 -1
Mg/m , µ = 0.264 mm , F(000) = 1016, Z = 4, monoclinic, space
group P21/c, T = 173(2) K, 16606 reflections collected, 5620
independent reflections, θmax 27.997°, 300 refined parameters,
(
(
1)
2)
Yet, L. Chem. Rev. 2000, 100, 2963.
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-
3
maximum residual electron density 0.352 and -0.374 e.Å . R =
1
0
.0497, wR = 0.1152. Crystallographic data for the structure
(3)
Schmidt, B.; Hauke, S.; Krehl, S.; Kunz, O.; in
2
have been deposited with the Cambridge Crystallographic Data
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,6-benzodiazonine 46: 2,5,6,7-tetrahydro-1H-1,6-
benzodiazonine 43 (0.030 g, 0.062 mmol) in benzene-d was
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6
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Rev. 2009, 109, 3743.
3
3
mmol) and the reaction mixture was stirred at 90 °C for 40 h. The

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