1-Aminobenzotriazole functionalisation using directed metallation: New routes to chromanes and chromenes using intramolecular benzyne trapping by alcohols

Article abstract of DOI:10.1039/b001834l

Metallation of 1-(tert-butoxycarbonylamino)benzotriazole 8 leads to the dianionic species 9 which undergoes smooth reactions with a range of electrophiles, under appropriate conditions. The derived iodide 30 undergoes efficient Sonogashira coupling with a range of alk-1-yn-3-ols to provide the expected arylalkynes 33, total or partial reduction of which leads to the arylpropanols 34 and the (Z)-allylic alcohols 40 respectively. N-Deprotection and exposure to N-iodosuccinimide then led to smooth benzyne generation and intramolecular trapping by the hydroxy functions with iodine incorporation to give the iodochromanes 35 and iodochromenes 41 respectively, in respectable overall yields. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b001834l

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1-Aminobenzotriazole functionalisation using directed metallation:
new routes to chromanes and chromenes using intramolecular
benzyne trapping by alcohols
1
David W. Knight and Paul B. Little
Chemistry Department, Cardiff University, P.O. Box 912, Cardiff, UK CF10 3TB
Received (in Cambridge, UK) 7th March 2000, Accepted 7th April 2000
Published on the Web 30th June 2000
Metallation of 1-(tert-butoxycarbonylamino)benzotriazole 8 leads to the dianionic species 9 which undergoes
smooth reactions with a range of electrophiles, under appropriate conditions. The derived iodide 30 undergoes
efficient Sonogashira coupling with a range of alk-1-yn-3-ols to provide the expected arylalkynes 33, total or partial
reduction of which leads to the arylpropanols 34 and the (Z)-allylic alcohols 40 respectively. N-Deprotection and
exposure to N-iodosuccinimide then led to smooth benzyne generation and intramolecular trapping by the hydroxy
functions with iodine incorporation to give the iodochromanes 35 and iodochromenes 41 respectively, in respectable
overall yields.
Despite being classic examples of reactive intermediates,
benzynes have enjoyed applications in a plethora of synthetic
pathways.1 However, one of the major drawbacks associated
with benzyne chemistry is the relative lack of general
approaches to substituted examples. As a contribution to this,
we have recently reported that the principle of lateral deproton-
ation2 can be used to facilitate the generation of the dianionic
species 2 from the parent aminobenzotriazole 1, using BuLi–
TMEDA in tetrahydrofuran at low temperature (Scheme 1).3
Subsequent condensations with aldehydes or epoxides, amongst
other electrophiles, provided excellent yields of the ortho-
substituted benzyne precursors 3 and 4 respectively, following
deprotection of the 1-amino group. The elaboration of these
species gave us the opportunity to explore the prospects for
trapping benzynes by hydroxy functions in an intramolecular
manner. Perhaps surprisingly, successful examples of this type
of transformation had not been reported to date, before these
studies, although many alkaloid syntheses have been reported
which rely on similar trapping, but by nitrogen nucleophiles.1
The classical methods for generating benzynes from 1-amino-
benzotriazoles rely on oxidation of the 1-amino group, using
either lead() acetate or N-bromosuccinimide;4 these are in
marked contrast to the more common and highly basic
methods for benzyne generation from halo- and dihalo-
benzenes. Hence, we were able to examine such intramolecular
trapping reactions using an unionized hydroxy function and it
seems likely that this is the basis of the resulting highly effi-
cient cyclisations of the presumed benzynes [5; n = 1,2] to the
dihydrobenzofurans [6; n = 1] and chromanes [6; n = 2].3 When
lead() acetate was used, unsubstituted products (6; X = H)
were obtained; however, a significant bonus when N-bromo-
succinimide was used as oxidant, was that an additional brom-
Scheme 1
DOI: 10.1039/b001834l
J. Chem. Soc., Perkin Trans. 1, 2000, 2343–2355
This journal is © The Royal Society of Chemistry 2000
2343

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ine atom was incorporated [i.e. 6; X = Br].4 This finding was
enhanced, both in terms of overall yield and synthetic utility,
with the discovery that N-iodosuccinimide (NIS) led very
efficiently to the corresponding iodides [6; X = I], thereby pro-
viding the potential for the introduction of a wide variety of
functional groups at this position. Although not proven, this
transformation may involve a hydrogen-bonded species 7;3 it
has also been suggested that an N-nitrene may be involved in
the pathway to the benzyne intermediates.4
The success of this scheme led us to consider more efficient
routes to the ortho-substituted 1-aminobenzotriazoles 3 and 4.
One of the drawbacks of the foregoing methods is associated
with the preparation of the starting material 1. Although the
chemistry, originally developed by Campell and Rees,4 is
relatively straightforward, reliable and efficient, five steps are
required to obtain the protected aminobenzotriazole 1 from
commercial 2-methyl-6-nitroaniline. We were attracted to the
idea that it might be possible to generate the parent dianion 9
from the more readily available aminobenzotriazole 8 (Scheme
1). Clearly, if this were viable, condensations with a variety of
electrophiles ought to be possible, although such sp2-centred
carbanions are usually less nucleophilic than similar sp3-centred
species such as dianion 2.5 What attracted us more was the
prospect of using dianion 9 to generate various intermediates
10 in which the added group ‘X’ would be a trialkyltin, halogen
or boronic acid residue, hence allowing the possibility of
homologations by various palladium(0)-catalysed processes
including the Stille, Suzuki, Heck and Sonogashira methods,
for example (Scheme 2). We anticipated that such couplings
later intermediates and products [11 to 13] could be accessed as
single enantiomers. In summary, this scheme overall can be
represented by the disconnections indicated in formula 14.
Both chromanes and chromenes are ubiquitous in nature and
display a wide range of biological activities, and many synthetic
approaches have been established to these compounds and their
analogues, although not all are amenable to the elaboration of
single enantiomers.8 More recently, purely synthetic derivatives,
such as cromakalim 15 have been found to be highly selective
and unique potassium channel activators.9 These have been
prepared from the corresponding chromenes 17, which in turn
are obtained from aryl propargyl† ethers 16 which undergo a
spectacular series of thermal reorganizations, initiated by a
Claisen rearrangement. This chromene synthesis, due originally
to Iwai and Ide,10 was often used with relish by Leslie Crombie
to test the mechanistic skills of his colleagues and co-workers
and it is no coincidence that one of the main players in the
discovery of cromakalim, G. Stemp, is an ex-member of the
Crombie group, which also made its own significant contri-
butions to chromene synthesis.11 Of course, one of the more
spectacular examples of the chromane ring found in nature
occurs in the insecticidal molecule rotenone 18, which was the
subject of a prolonged series of seminal biosynthetic studies by
Crombie and Whiting12 and often referred to by Crombie as
“the queen of molecules”. Herein, we report in full our recent
contribution to both chromane and chromene synthesis, based
on the benzyne chemistry outlined above.13
Scheme 2
Results and discussion
could be used to access a range of unsaturated derivatives 11,
for example, and thence the saturated or (Z)-allylic systems
12, the latter either directly or by alkyne semi-reduction, and
finally the chromane and chromene derivatives 13, following
N-deprotection, benzyne generation using NIS and intra-
molecular cyclisation. We reasoned that this scheme would
offer a number of advantages. Firstly, the intermediates 10
could be available efficiently in only three steps from very cheap,
commercially available benzotriazole (see below), given that
these steps could be optimized or, in the case of the last metal-
lation step, that the dianion 9 could indeed be generated and
displayed the required reactivity.6 Secondly, such couplings
would add a further degree of flexibility to our initial routes
based on dianion 2 and, significantly, would obviate the need
to expose potentially sensitive and more complex addends to
strongly basic conditions. Finally, more asymmetric approaches
to alk-1-yn-3-ols have been established7 and hence all the
The first objective was to define an optimized route to 1-amino-
benzotriazole 20. The method favoured by Campbell and Rees
during their seminal work in this area4 was a four step process,
starting from 2-nitroaniline (see above). While successful in our
hands and although the chemistry is amenable to large-scale
preparations, the overall yield was ca. 20% and the intermedi-
ates were poorly crystalline and not particularly easy to handle.
A much briefer alternative appeared to be direct N-amination
of benzotriazole 19 using hydroxylamine-O-sulfonic acid as
the electrophile in hot (80 ЊC) aqueous potassium hydroxide.4
However, this is not without its problems, as the corresponding
2-isomer 21 is formed as a by-product, amounting to approxi-
mately 25% of the product under these aqueous conditions
(Scheme 3). Attempts to modify this reaction were restricted
† IUPAC name for propargyl is prop-2-ynyl.
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Table 1 Generation of dianion 9: optimisation and trapping by Bu3SnCla
Entry
Base
Additive
Solvent
Ratio of products
23
0
64
71
61
0
44
100
23
89
99
8
100
36
29
39
100
56
0
1
2
3
4
5
6
7
8
9
BuLi
—
THF
THF
Et2O
THF
THF
THF
THF
THF
THF
THF
BuLib
BuLi
TMEDA
TMEDA
—
—
—
12-Crown-4
20 mol% 12-c-4
Tetraglyme
Tetraglymec
t-BuLi
LDA
t-BuOK–BuLi
BuLi
BuLi
BuLi
77
11
1
10
BuLi
a Reactions were performed at Ϫ78 ЊC using 2.2 equivalents of the base and additive, unless stated otherwise. The ratios of products were for
essentially quantitative material balances and were determined from 1H NMR integrations. b When 3.3 equivalents of base and additive were used,
the result was almost identical. c 5 equivalents of tetraglyme were used.
Scheme 3
Scheme 4
to relatively low temperatures because rearrangement of the
1-amino isomer 20 to the 2-isomer 21, which is not a benzyne
precursor, becomes significant above ca. 50 ЊC.4,14 Thus, all
modifications were carried out by careful addition of the
sulfonic acid to a solution of benzotriazole 19, allowing the
natural exotherm to keep the temperature of the reaction
mixture at 50 ЊC. Under these conditions in water, the desired
1-isomer 20 was obtained selectively, but in only 32% yield.
Surprisingly, in ethanol, the conversion was nearly quantitative,
but the product was formed in a 2:1 ratio in favour of the
unwanted 2-isomer 21. The reaction failed in acetonitrile but
regioselectively delivered a 62% yield of the 1-isomer 20 in
dioxane containing 5% water. (In pure dioxane, the reaction had
a dangerous tendency to produce uncontrollable exotherms.)
Eventually, guided by literature reports of the N-amination of
indole,15 we found that dimethylformamide (DMF) containing
5% water, again to allow moderation of the exotherm, was
an optimum solvent system, delivering around 70% of the
1-isomer 20, uncontaminated by the 2-isomer 21. Dilution of
the DMF with toluene to assist in the work-up failed, as little
reaction occurred. Final isolation of the aminobenzotriazole 20
was achieved by evaporation and purification via its hydro-
chloride or by filtration through silica gel using a solvent gradi-
ent. In common with the corresponding 7-methyl derivative 1,3
it proved impossible to add a single butoxycarbonyl (Boc)
group to the highly nucleophilic amino function in amino-
benzotriazole 20. Instead, treatment with two equivalents of di-
tert-butyl dicarbonate [Boc2O] delivered excellent yields of the
bis-Boc derivative 22, which was then selectively and efficiently
hydrolysed using aqueous methanolic sodium hydroxide at
50 ЊC to give the required N-Boc derivative 8. Fortunately, this
whole process could be carried out in a single flask and hence
was only wasteful of the Boc2O reagent (Scheme 4).
known to react unambiguously with carbon nucleophiles and
also because this would provide one of the desired intermedi-
ates [10; X = SnBu3 ( = 23)] for the projected Pd(0)-catalysed
coupling reactions (Scheme 2). The initial results are presented
in Table 1. In all cases, the whole process was performed using
2.2 equivalents of both the base and any additive (usually in
tetrahydrofuran at Ϫ78 ЊC) until the electrophile had been
added, when the mixture was allowed to warm slowly to ambi-
ent temperature. Product ratios, for what were essentially quan-
titative material balances, were deduced from the integrals of
1H NMR spectra of the crude products. Butyllithium alone was
ineffective (entry 1) but in the presence of N,N,NЈ,NЈ-tetra-
methylethylenediamine (TMEDA) it delivered an encouraging
2:1 ratio in favour of the desired product 23 (entry 2).3 Use of
ether as solvent or tert-butyllithium as base gave results similar
to this (entries 3, 4) while lithium diisopropylamide failed to
give any of the desired dianion 9 (entry 5), and Schlosser’s
base16 gave a 1:1 mixture (entry 6). It was only when we turned
to ether-based additives that improvements were achieved.
Thus, the addition of 2.2 equivalents of 12-crown-4 gave an
essentially quantitative conversion (entry 7) but, unfortunately
when only 20 mol% was used, this reverted to a very poor yield
of product (entry 8). On the grounds of both toxicity and
expense, we were not keen to use such quantities of a crown
ether and therefore we tested tetra(ethylene glycol) dimethyl
ether (tetraglyme) as an alternative additive. Although these
open-chain analogues of crown ethers are understandably
less effective, their relative cheapness and ease of removal
offer significant advantages.17 In line with this, addition of
2.2 equivalents of tetraglyme gave a 9:1 ratio in favour of
the desired product 23 (entry 9), improved to an essentially
quantitative yield when this was increased to 5 equivalents
(entry 10).
We were therefore in a position to study the central metal-
lation idea, that of generating the dianion 9 (Scheme 1). We
used tributyltin chloride as a test electrophile, both because it is
Having established conditions for the seemingly quantitative
generation of the deep purple dianion 9, we tested its reactivity
J. Chem. Soc., Perkin Trans. 1, 2000, 2343–2355
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Table 2 Reactions of dianion 9 with electrophiles
Isolated yield (%)
No CeCl3
Electrophile
Compound
E
With CeCl3
Bu3SnCl
p-MeOC6H4CHO
DMF
(MeO)3B
C5H11CHO
23
24
25
26
27
28
Bu3Sn
p-MeOC6H4CH(OH)
CHO
[(MeO)2B]
C5H11CH(OH)
96
79
67
[71]
20
75
—
95
95
—
79
87
PrCH᎐CHCHO
PrCH᎐CHCH(OH)
᎐
᎐
29
—
73
C6F13I
NIS
1,2-Diiodoethane
30
30
30
I
I
I
29
27
—
55
—
97
with a range of electrophiles. The results are presented in Table
2 and showed, initially, a rather disappointing outcome. While
unambiguous electrophiles such as a benzaldehyde, DMF and
trimethyl borate gave 70–80% yields, an enolizable aldehyde
(hexanal) and various iodonium sources gave very poor returns,
although (E)-hex-2-enal gave a good yield of the [1,2]-adduct,
indicating at least that dianion 9, under these conditions, is a
hard nucleophile. As the poor yield obtained using hexanal as
the electrophile was most likely due to dianion 9 acting as a
base rather than a nucleophile, we reasoned that conversion to
a more nucleophile cerium() species could improve matters,
a phenomenon which has been exemplified many times,18
although it was very uncertain if this would be effective in the
case of dianion 9. In the event, lithium–cerium exchange was
effected by the combination of a solution of dianion 9 with a
suspension of cerium() chloride at Ϫ78 ЊC in THF, followed
by slow warming to 0 ЊC during 3 h. We were pleased to find
that the modified species delivered significantly improved yields
in all examples studied (Table 2). Enolization of a saturated
aldehyde was evidently much reduced and an excellent 73%
isolated yield was even obtained from cyclohex-2-enone. Tri-
methyl borate also reacted smoothly according to NMR anal-
ysis, although the final, presumed boronic acid was not isolated
in a pure state. With modifications to the work-up procedure, it
is likely that this will open the way for homologations of the
product 26 using the Suzuki method. One limitation was the
efficient incorporation of iodine: of a variety of electrophilic
iodine sources tried, the best was iodoperfluorohexane which
delivered only a 55% yield of the desired iodide 30. It was only
when we employed 1,2-diiodoethane as iodonium source and
substituted the five equivalents of tetraglyme with a similar
quantity of TMEDA that an essentially quantitative yield was
obtained. It was also possible to prepare iodide 30 from the
stannane 23 by a simple and highly efficient exchange using
molecular iodine in dichloromethane. However, problems with
removal of the tin residues from this two-step approach clearly
rendered it far less attractive. Both these species could be useful
in palladium-catalysed homologations. In contrast, the alde-
hyde derivative 25 represents a contrasting electrophilic inter-
mediate and hence offers alternative synthetic possibilities. We
have not yet explored this, beyond carrying out a Wittig homo-
logation to the unsaturated ester 31 and then a hydrogenation
to provide the propanoate 32 (Scheme 5).
Scheme 5
route to iodide 30, we chose to focus on this intermediate and
its suitability in Sonogashira couplings19 with alk-1-ynes, as
this appeared to offer a wide range of options and would allow
us to pursue the original aim, as set out in Scheme 2. However,
we were concerned that iodide 30 might not be an ideal partici-
pant in such couplings, as it is rather electron rich. This proved
well founded as attempted couplings between iodide 30 and
propargyl alcohol were unproductive at ambient temperature
and it was only when we turned to a combination of 20 mol%
each of (Ph3P)4Pd and copper() iodide under reflux in THF
that excellent yields were secured with a general series of
propargylic alcohols (Table 3). The one exception was found
when using 1-phenylprop-2-yn-1-ol when the major product
was ketone 39, presumably derived from Meyer–Shuster
In view of the now highly efficient and effectively three-step
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Table 3 Chromane synthesis
Substituents
Isolated yields of
saturated alcohols
34 (%)
Isolated yields of
iodochromans
35 (%)
Isolated yields of
alkynols 33 (%)
R1
R2
a
b
c
d
e
f
H
Et
Me
Ph
H
H
Me
H
H
92
91
87
38
81
72
78 [36a]
76 [36b]
95
96
95
—
0
92
95 [37a]
97 [37b]
86
85
90
—
—
78
—
—
p-MeOC6H4
CH2OH
[See structure 36a]
[See structure 36b]
Me
rearrangement of the initial product 33d. Oddly, the related
p-methoxy derivative 33e, which might be expected to be more
prone to this rearrangement, was obtained in excellent yield. We
assume that acid contamination from an unknown source was
responsible; in view of the subsequent problems with this type
of intermediate, this aspect was not pursued further. Com-
pounds 33 could also be obtained, but in poorer yields (ca. 50–
60%), by using a modified Castro–Stevens method20 in which
an isolated copper acetylide was reacted with iodide 30 in hot
pyridine in the presence of (Ph3P)4Pd.21 At ambient temper-
ature in CDCl3, the NMR spectra of intermediates 33 were very
broadened, presumably because of rotamers, but were suf-
ficiently sharpened at 55–60 ЊC to permit analysis. Subsequent
hydrogenations to the corresponding saturated chromane pre-
cursors 34 proceeded smoothly using 10% Pd–C in methanol
and one atmosphere of hydrogen (Table 3), except in the case
of the aryl-substituted compound 33e, when no recognizable
products were obtained, presumably due to the sensitivity of
the benzylic alcohol function. Finally, we were delighted to find
that sequential N-deprotection and exposure of the resulting
N-aminobenzotriazoles to N-iodosuccinimide, as previously
described,3 led to excellent overall yields of the iodochromanes
35. This final two-step transformation could also conveniently
be carried out without isolation of the intermediate free base.
While the higher homologues 36 were both converted efficiently
into the saturated species 37 and thence into the free amines,
these both failed to cyclize in anything above trace yields and
instead gave moderate yields of the diiodides 38, which were
only partly characterized by NMR and mass spectral data. This
selectivity is further illustrated in the highly efficient cyclisation
of the diol 34f to the 2-hydroxymethylchromane 35f. In this
case, a tertiary alcohol competes successfully with a primary
alcohol in the formation of a six- rather than a seven-membered
ring. Clearly, the formation of seven and perhaps larger rings
may be possible using this methodology, in cases with more
conformationally restricted side chains. In the present cases, the
reactions leading to chromanes are highly efficient in cases of
primary, secondary and tertiary alcohols having aliphatic sub-
stituents but, as yet, fail with aryl substituents at the reduction
stage. Efforts to resolve this are underway.
Finally, we investigated the prospects of partial reduction of
the alkynols 33, with a view to defining a novel approach to
chromenes (Scheme 2). Using the unsubstituted alkynol 33a
as a test substrate, we found that Lindlar reduction was highly
J. Chem. Soc., Perkin Trans. 1, 2000, 2343–2355
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Table 4 Chromene synthesis
Substituents
R1
Isolated yields of
iodochromenes
41 (%)
Isolated yields of
(Z)-alkenols 40 (%)
R2
a
b
c
d
e
H
Et
H
H
Me
Me
H
99a
94
80
60
0
75
83
0
63
—
Me
CH2OH
p-MeOC6H4
a Using a Lindlar reduction.
effective in producing the required (Z)-allylic alcohol 40a
(Table 4) when quinoline was used as the catalyst modifier.22
Happily, the product delivered an encouraging 75% isolated
yield of the parent iodochromene 41a when treated sequentially
with TFA and NIS under the established conditions, thus estab-
lishing the principle of this new approach at least. However, the
Lindlar method was neither easily reproduced nor amenable to
scale-up, despite many attempts and modifications. Similarly,
with more substituted intermediates 33b–f, such reductions
were highly capricious. A search for alternatives led us to try
reductions with titanocene dichloride and isobutylmagnesium
chloride which has previously been used to obtain (Z)-allylic
alcohols.23 However, this was not successful; although the
(Z)-alkene function was produced, loss of the Boc tert-butyl
group also occurred. Subsequent attempts to obtain the free
amine led to unrecognizable products. We then turned to the
use of Rieke zinc24 and were delighted to obtain excellent yields
of the required allylic alcohols 40a–d (Table 4). In contrast to
the brief reaction times reported in the literature,24 we found
much lengthier periods were necessary to secure these conver-
sions. Two factors were important: firstly, that all the initial
potassium metal was completely reacted and secondly, that the
acetylenic alcohol was not contaminated with traces of tri-
phenylphosphine from the foregoing Sonogashira coupling.
One limitation was that such a reduction of the aryl substituted
propargylic alcohol 33e led to a gross mixture of products,
presumably due to the hydrogenolytic sensitivity of the benzylic
C–O bond. Subsequent removal of the N-Boc group using TFA
and exposure of the resulting free amines to N-iodosuccinimide
then led smoothly to the iodochromenes 41a,b,d, thus establish-
ing that the second idea indicated in Scheme 2 is indeed viable.
One limitation was that the sensitive tertiary allylic alcohol
function in precursor 40c underwent dehydration rather than
simple deprotection; had this step provided the desired alcohol,
we were confident that cyclisation would be successful, in view
of the successful formation of chromane 35c (Table 3). Finally,
the diol derivative 34f underwent cyclisation exclusively at the
tertiary hydroxy function and none of the seven-membered
ether derived from the adjacent primary hydroxy group was
observed, as was the case with the related chromane formation
(Table 3).
of delicate and enantiopure side chain arrays ready for cyclis-
ation and which could avoid the potentially troublesome and
somewhat limiting alkyne reduction step. It may also prove pos-
sible to exchange the Boc group prior to the coupling step and
thereby obviate the requirement for exposure to acidic condi-
tions necessary to free the amine function, which has resulted in
some limitations to the present scheme. Further studies are also
in progress aimed at extending this type of chemistry to more
highly substituted examples.
Experimental
General details
Melting points were determined on a Kofler hot stage apparatus.
Infra-red spectra were recorded on a Perkin-Elmer 1600 series
FTIR spectrometer using KBr discs for solid samples and thin
films between NaCl plates in the cases of liquid samples. NMR
spectra were recorded on a Bruker DPX 400 instrument oper-
ating at 400 MHz for 1H spectra and 100 MHz for 13C spectra.
Unless otherwise stated, all such spectra were recorded at 300 K
using dilute solutions in deuteriochloroform. Proton chemical
shifts were determined relative to both tetramethylsilane (δH
0.00) and chloroform (δ 7.27) while carbon shifts were corrected
to tetramethylsilane (δC 0.00) and the centre line of chloroform
(δC 77.3). Coupling constants (J) are quoted in hertz (Hz)
and multiplicities are expressed by the usual conventions;
‘br’ refers to a broadened resonance. Molecular weights and
low resolution mass spectra were determined using a Fisons
VG Platform II Quadrupole instrument using electrospray
ionization (ES) unless otherwise stated. APcI = atmospheric
pressure chemical ionization. High resolution data were
obtained courtesy of the EPSRC Mass Spectrometery Service
at University College, Swansea, using the ionization methods
specified. Microanalyses were obtained using a Perkin-Elmer
240C Elemental Analyzer.
Unless otherwise stated, reactions were performed under an
atmosphere of dry nitrogen. Solvents and reagents were puri-
fied by the usual methods;25 all electrophiles were purified
immediately prior to use. ‘Petrol’ refers to the fraction with bp
40–60 ЊC and ‘ether’ refers to diethyl ether. All organic solu-
tions from work-ups were dried by brief exposure to dried
magnesium sulfate. Column chromatography, referred to as
‘CC’, was carried out using Matrex Silica (35–70 µm) silica gel
and the solvents specified. Where relevant, all compounds
referred to below were racemates.
In summary, the efficient synthesis of the stannane 23 and
iodide 30 opens up a new strategy for both chromane and
chromene synthesis. It seems likely that the Sonogashira-based
method illustrated herein can be augmented by related coupling
reactions, all of which have the potential for the incorporation
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1-Aminobenzotriazole 20
1-(tert-Butoxycarbonylamino)benzotriazole 8
Method A. Hydroxylamine-O-sulfonic acid (94.9 g, 840.2
mmol) was added portionwise to a stirred solution of benzo-
triazole 19 (50.0 g, 420.1 mmol) and potassium hydroxide
(117.6 g, 2.1 mol) in water (500 ml) such that the temperature of
the reaction mixture remained below 50 ЊC (ca. 1.0 g minϪ1).
After the addition was complete, the mixture was cooled to
ambient temperature and stirring continued for a further 1 h.
The resulting precipitate was removed by vacuum filtration
and washed thoroughly with ether. The filtrate was separated
and the aqueous layer extracted with ether (5 × 100 ml).
The combined ether solutions were dried and evaporated to
leave crude amine 20. This was dissolved in a minimum of
2 M hydrochloric acid and the resulting solution kept at Ϫ2 ЊC
overnight during which time 1-aminobenzotriazole hydro-
chloride crystallized and was removed by filtration. The solid
was dried under vacuum and showed mp 131–134 ЊC and was
>95% pure according to 1H NMR data. The free amine
was obtained by direct basification of the solid salt using 2 M
aqueous sodium hydroxide followed by extraction with ether
(3 × 100 ml). The combined extracts were dried and evaporated
to leave the amine 20 (18.1 g, 32%) as a colourless solid,
mp 84 ЊC [lit.4 mp 84 ЊC].
a) From 1-[N,N-bis(tert-butoxycarbonyl)amino]benzotriazole
22. Aqueous 2 M sodium hydroxide (200 ml) was added slowly
to a stirred solution of the bis-Boc aminobenzotriazole 22
(89.9 g, 272.5 mmol) in methanol (200 ml) maintained at 50 ЊC.
After 2 h, the solution was cooled and evaporated. The residue
was cooled in ice and carefully neutralised using ice-cold 2 M
hydrochloric acid. The resulting solution was extracted with
ether (5 × 100 ml) and the combined extracts washed with
saturated aqueous sodium hydrogen carbonate (50 ml), water
(50 ml) and brine (50 ml), then dried and evaporated. Crystal-
lization of the residue from dichloromethane–petrol (1:1) gave
the mono-Boc derivative 8 (60.2 g, 94%) as colourless crystals,
mp 102–104 ЊC [Found: C, 56.47; H, 6.16; N, 24.06. C11H14N4O2
requires C, 56.38; H, 6.03; N, 23.93%], νmax/cmϪ1 3420, 2110,
1760, 1740 and 1630; δH 1.48 (9H, s, But), 7.41 (1H, t, J 6.8,
5-H), 7.50–7.71 (2H, m, 6- and 7-H), 8.03 (1H, t, J 8.0, 4-H) and
8.39 (1H, br s, NH); δC 28.4 (C(CH3)3), 83.9 (C(CH3)3), 109.4,
120.6, 124.9, 129.0 (all CH), 133.0, 144.6 (both C) and 153.8
(CO); m/z 235 (Mϩ ϩ H, 100%) and 179 (47).
b) One-pot procedure. A solution of di-tert butyl dicarbonate
(139.1 g, 637.8 mmol) in dry acetonitrile (100 ml) was added
during 10 min to a stirred solution of 1-aminobenzotriazole 20
(38.8 g, 289.9 mmol) and DMAP (0.707 g) in dry acetonitrile
(300 ml) maintained at 0 ЊC. The cooling bath was removed and
the solution stirred for 1 h, then heated to 50 ЊC and treated
with 2 M aqueous sodium hydroxide (200 ml). The resulting
mixture was stirred vigorously at this temperature for 1 h then
cooled and evaporated. Subsequent work-up as described above
gave the mono-Boc derivative 8 (64.4 g, 95%), identical to the
foregoing sample.
Method B. The method was exactly as described in Method A
except that dimethylformamide (250 ml) and water (12 ml) were
used as solvent. The rate of addition was essentially the same;
following removal and washing of the precipitate as described
above, the filtrate was evaporated to dryness using a rotary
evaporator attached to a rotary pump. The temperature of the
water bath was kept below 50 ЊC; above this, rearrangement to
the corresponding 2-amino isomer 21 became significant. The
residue was purified via the hydrochloride salt, as in Method A,
to give the amine 20 (38.8 g, 69%) which showed identical
properties to the foregoing material.
Metallation and homologation of 1-(tert-butoxycarbonylamino)-
benzotriazole 8
General procedure A. Butyllithium (2.2 equivalents of a 1.6
M solution in hexanes) was added dropwise to a stirred solution
of dry tetraglyme (1.5 ml mmolϪ1 of benzotriazole 8) in
dry tetrahydrofuran (10 ml mmolϪ1 of 8) cooled in a dry
ice–acetone bath. After 0.5 h, a solution of 1-(tert-butoxy-
carbonylamino)benzotrizole 8 (1 equivalent) in dry tetrahydro-
furan (10 ml mmolϪ1 of 8) was added dropwise. The resulting
deep purple solution was stirred below Ϫ70 ЊC for 0.5 h before
the addition of an electrophile (1.1 equivalents) dissolved in
tetrahydrofuran (1 ml mmolϪ1). The resulting solution was
warmed to ambient temperature during 0.5 h then stirred for
1 h before quenching by the addition of saturated aqueous
ammonium chloride (10 ml mmolϪ1 of 8) followed by acidifi-
cation using 2 M hydrochloric acid. The resulting mixture
was extracted with ether (3 × 30 ml mmolϪ1). The combined
extracts were washed with saturated aqueous sodium hydrogen
carbonate (10 ml mmolϪ1), water (10 ml mmolϪ1) and brine
(10 ml mmolϪ1), then dried and evaporated. CC of the residue
(ca. 20 g silica per mmol) in petrol–ether (7:3), unless otherwise
stated, separated the pure product.
Alternative purification of amine 20. The crude amine 20
isolated following the evaporation step in method B was
absorbed onto silica gel (250 g), slurried in a large sinter funnel
with petrol. The surface was covered with acid-washed sand
and the silica eluted with petrol (1 l) with the aid of a water
pump, followed by ether–petrol mixtures of the same volume,
starting with 10% ether–petrol and increasing to neat ether.
The amine was eluted in the fractions containing 70% ether
up to neat ether. Evaporation of the combined fractions
gave pure amine 20 (36.2 g, 64%), identical to the foregoing
material.
1-[N,N-Bis(tert-butoxycarbonyl)amino]benzotriazole 22
A solution of di-tert-butyl dicarbonate (139.1 g, 637.8 mmol) in
dry acetonitrile (100 ml) was added dropwise during 10 min to
a stirred solution of 1-aminobenzotriazole 20 (38.8 g, 289.9
mmol) and 4-(dimethylamino)pyridine (DMAP; 0.707 g, 5.8
mmol) in dry acetonitrile (300 ml) maintained at 0 ЊC. The
cooling bath was then removed and the resulting solution
stirred for 1 h before the solvent was evaporated. The residue
was dissolved in ether (300 ml) and the resulting solution
washed successively with saturated aqueous sodium hydrogen
carbonate (50 ml), water (50 ml) and brine (50 ml), then dried
and evaporated to leave a beige gum. Crystallization from
ether–petrol (1:1) gave the bis-BOC derivative 22 (89.9 g, 94%)
as colourless crystals, mp 134–136 ЊC [Found: C, 57.55; H, 6.61;
N, 16.91. C16H22N4O4 requires C, 57.46; H, 6.64; N, 16.76%],
νmax/cmϪ1 1771, 1619, 1475, 1457, 1396, 1372, 1347, 1248, 1124,
1006 and 912; δH 1.37 (18H, s, 2 × But), 7.40–7.51 (2H, m,
5- and 7-H), 7.59 (1H, t, J 8.1, 6-H) and 8.10 (1H, d, J 8.1, 4-H);
δC 28.1 (2 × C(CH3)3), 86.3 (2 × C(CH3)3), 108.6, 121.0, 125.0,
129.4 (all CH), 132.4, 144.5 (both C) and 148.7 (2 × CO),
m/z (APcI) 335 (Mϩ ϩ H, 100%).
General procedure B. Anhydrous cerium() chloride was
prepared from the heptahydrate by drying in a vacuum oven at
140 ЊC and 0.1 mmHg for 4 days with regular turning and
crushing of the sample. The dry salt (1.1 equivalents) was
slurried in dry tetrahydrofuran (30 ml mmolϪ1) for 16 h. In a
separate flask, butyllithium (2.2 equivalents of a 1.6 M solution
in hexanes) was added to a stirred solution of dry tetraglyme (5
equivalents) in dry tetrahydrofuran (10 ml mmolϪ1) maintained
below Ϫ70 ЊC using a dry ice–acetone bath. After 0.5 h, a
solution of 1-(tert-butoxycarbonylamino)benzotriazole 8 (1
equivalent) in dry tetrahydrofuran (10 ml mmolϪ1) was added
dropwise. The resulting deep purple solution was stirred at the
same temperature for 0.5 h. During this period, the cerium()
J. Chem. Soc., Perkin Trans. 1, 2000, 2343–2355
2349

View Article Online
chloride suspension was cooled in a dry ice–acetone bath and
titrated with butyllithium (1.6 M in hexanes) until a faint but
permanent orange colour appeared; typically this required 0.1
ml mmolϪ1. The purple dianion solution was then rapidly
transferred via syringe into the cerium() chloride suspension.
The resulting mixture was slowly warmed to 0 ЊC during 3 h
then recooled to Ϫ78 ЊC and treated with a solution of an elec-
trophile (1.1 equivalents) in tetrahydrofuran (1 ml mmolϪ1).
The mixture was then allowed to warm slowly to ambient tem-
perature and stirred for 16 h before quenching with saturated
aqueous ammonium chloride (10 ml mmolϪ1 of 8), followed by
work-up as described in general procedure A.
ether–petrol), νmax/cmϪ1 3400, 2931, 1737, 1458, 1371, 1254,
1158, 909 and 734; δH 0.94 (3H, t, J 5.2, 6Ј-CH3), 1.18–1.34 (6H,
m, 3 × CH2), 1.37–1.57 (9H, br s, But), 1.60–1.75 (2H, m, 2Ј-
CH2), 3.65–4.00 (1H, br res, OH), 5.18 (1H, br t, J 5.2 CHOH),
7.15 (1H, t, J 7.1, 5-H), 7.43 (1H, d, J 7.1, 6-H), 7.67 (1H, d,
J 7.1, 4-H) and 9.45–9.63 (1H, br s, NH); δC 14.4 (6Ј-CH3),
23.0 (5Ј-CH2), 25.8 (4Ј-CH2), 28.4 (C(CH3)3), 31.9 (3Ј-CH2),
38.3 (2Ј-CH2), 69.7 (CHOH), 84.0 (C(CH3)3), 119.2, 124.9,
126.1 (all CH), 129.2, 129.8, 144.9 (all C) and 154.5 (CO); m/z
335 (Mϩ ϩ H, 100%) and 279 (13) [Found: Mϩ ϩ H, 335.2089.
C17H27N4O3 requires M, 335.2083].
(E)-1-(tert-Butoxycarbonylamino)-7-(1Ј-hydroxyhex-2Ј-en-1Ј-
yl)benzotriazole 28
1-(tert-Butoxycarbonylamino)-7-tributylstannylbenzotriazole 23
By general procedure B, treatment of dianion 9 (1.0 mmol)
with (E)-hex-2-enal (0.12 ml, 1.1 mmol) gave the allylic alcohol
28 (0.289 g, 87%) as a colourless solid, mp 138–144 ЊC (from
ether–petrol) [Found: C, 61.27; H, 7.42; N, 16.88. C17H24N4O3
requires C, 61.41; H, 7.28; N, 16.86%], νmax/cmϪ1 3264, 2960,
2932, 2873, 1753, 1457, 1394, 1370, 1252, 1160, 1116, 1048, 969
and 907; δH 0.78 (3H, t, J 7.4, 6Ј-CH3), 1.28 (2H, quintet, J 7.4,
5Ј-CH2), 1.35–1.50 (9H, br s, But), 1.94 (2H, q, J 7.4, 4Ј-CH2),
3.25–3.51 (1H, br res, OH), 5.58 (1H, d, J 6.0, CHOH), 5.61
(1H, dt, J 15.0 and 7.4, 3Ј-H), 5.72 (1H, dd, J 15.0 and 6.0,
2Ј-H), 7.19 (1H, t, J 7.1, 5-H), 7.41 (1H, d, J 7.1, 6-H), 7.72 (1H,
d, J 7.1, 4-H) and 8.95–9.05 (1H, br s, NH); δC 13.8 (6Ј-CH3),
22.2 (5Ј-CH2), 28.1 (C(CH3)3), 34.4 (4Ј-CH2), 70.5 (CHOH),
83.8 (C(CH3)3), 120.0, 124.5, 126.7 (all CH), 126.7, 129.8 (both
C), 130.3, 134.2 (both CH), 145.2 (C) and 153.9 (CO); m/z 333
(Mϩ ϩ H, 100%) and 98 (92).
By general procedure A, treatment of dianion 9 generated from
benzotriazole 8 (0.234 g, 1.0 mmol) with tributyltin chloride
(0.30 ml, 1.11 mmol) gave the stannane 23, initially as a brown
solid which, following crystallization from ether–petrol, gave
pure material (0.501 g, 96%) as a colourless solid, mp 127–
130 ЊC [Found: C, 51.51; H, 8.00; N, 10.36. C23H40N4O2Sn
requires C, 52.65; H, 7.69; N, 10.68%], νmax/cmϪ1 3180, 2960,
2919, 1749, 1425, 1335, 1195 and 1105; δH 0.88 (9H, t, J 7.4,
3 × Me), 1.19 (6H, app. t, J 7.4, 3 × CH2), 1.29–1.39 (6H, m,
3 × CH2), 1.45–1.82 (15H, m, 3 × CH2Sn and But), 7.37 (1H,
dd, J 7.5 and 7.5, 5-H), 7.56 (1H d, J 7.5, 6-H), 8.01 (1H, d,
J 7.5, 4-H) and 8.13 (1H, br s, NH); δC 11.0 (CH2), 14.1 (CH3),
27.2 (CH2), 28.5 (C(CH3)3), 29.4 (CH2), 83.9 (C(CH3)3), 120.5
(CH), 121.7 (C), 124.8 (CH), 129.5 (C), 138.4 (CH), 143.1 (C)
and 154.9 (CO); m/z 528 (20), 526 (23), 525 (Mϩ(Sn120) ϩ H,
100%), 523 (72), 522 (38), 469 (40), 467 (28), 465 (18) and 235
(28).
1-(tert-Butoxycarbonylamino)-7-(1Ј-hydroxycyclohex-2Ј-en-1Ј-
yl)benzotriazole 29
1-(tert-Butoxycarbonylamino)-7-[1Ј-hydroxy-1Ј-(4-methoxy-
phenyl)methyl]benzotriazole 24
By general procedure B, treatment of dianion 9 (1.0 mmol) with
cyclohex-2-enone (0.106 ml, 1.1 mmol) gave the allylic alcohol
29 (0.24 g, 73%) as a colourless solid of indeterminate mp due
to decomposition, νmax/cmϪ1 3216, 2976, 2934, 2869, 1755,
1480, 1370, 1255, 1158, 915 and 734; δH 1.45–1.62 (9H, br s,
But), 1.65–1.72 (1H, br res, 5Ј-Ha), 1.78 (1H, dddd, J 11.5, 5.7,
5.7 and 2.0, 5Ј-Hb), 2.03–2.09 (2H, m), 2.12–2.30 (2H, m), 2.79–
2.83 (1H, br res, OH), 5.84 (1H, br d, J 10, 2Ј-H), 6.20 (1H,
dt, J 10.0 and 3.7, 3Ј-H), 7.30 (1H, t, J 8.1, 5-H), 7.39 (1H, d,
J 8.1, 6-H), 7.95 (1H, dd, J 8.1 and 0.9, 4-H) and 9.42–9.51
(1H, br s, NH); δC 19.3, 25.1 (both CH2), 28.5 (C(CH3)3), 38.3
(CH2), 73.9 (COH), 83.7 (C(CH3)3), 120.5, 124.1, 127.2 (all CH;
one C obscured), 130.7 (C), 131.1, 133.0 (both CH), 146.5 (C)
and 154.1 (CO); m/z 331 (Mϩ ϩ H, 100%).
By general procedure B, reaction between dianion 9 on a 1.0
mmol scale with p-anisaldehyde (0.12 ml, 1.1 mmol) gave the
alcohol 24 (0.351 g, 95%) as colourless crystals, mp 153–154 ЊC
(from ether–petrol) [Found: C, 61.35; H, 5.96; N, 15.18.
C19H22N4O4 requires C, 61.61; H, 5.99; N, 15.13%], νmax/cmϪ1
3406, 2253, 1740, 1251, 1157, 911 and 738; δH 1.33–1.52 (9H, br
s, But), 3.75 (3H, s, OMe), 6.26 (1H, s, CHOH), 6.79 (2H, d,
J 8.7, 2 × ArH), 7.17 (2H, d, J 8.7, 2 × ArH), 7.35 (1H, t, J 7.5,
5-H), 7.47 (1H, d, J 7.5, 6-H), 7.95 (1H, d, J 7.5, 4-H) and 8.61
(1H, s, NH); δC 28.5 (C(CH3)3), 56.1 (OCH3), 72.4 (CHOH),
84.2 (C(CH3)3), 114.5 (CH), 121.8 (C), 124.2 (CH), 126.1 (C),
127.2, 128.5 (both CH), 130.1 (C), 134.2 (CH), 146.1, 153.2
(both C) and 159.9 (CO); m/z 371 (Mϩ ϩ H, 100%) and 353
(16).
1-(tert-Butoxycarbonylamino)-7-iodobenzotriazole 30
1-(tert-Butoxycarbonylamino)-7-formylbenzotriazole 25
By general procedure B, but using N,N,NЈ,NЈ-tetramethyl-
ethylenediamine (5 equivalents) in place of tetraglyme, treat-
ment of dianion 9 (1 mmol) with 1,2-diiodoethane (0.282 g, 1.1
mmol), added as a solution in tetrahydrofuran (10 ml) gave the
iodide 30 (0.349 g, 97%) as a colourless solid, mp 142–144 ЊC
(from petrol–ether) [Found: C, 36.97; H, 3.48; N, 15.85.
C11H13IN4O2 requires C, 36.67; H, 3.64; N, 15.56%], νmax/cmϪ1
3295, 2990, 1762, 1735, 1582, 1485, 1370, 1275, 1250 and 1154;
δH 1.22–1.58 (9H, br s, But), 7.05 (1H, t, J 7.8, 5-H), 7.86 (1H,
d, J 7.8, 6-H), 7.95 (1H, d, J 7.8, 4-H) and 8.91–9.02 (1H, br s,
NH); δC 28.7 (C(CH3)3), 71.0 (CI), 84.3 (C(CH3)3), 121.1, 126.7
(both CH), 132.5 (C), 139.9 (CH), 144.9 (C) and 153.3 (CO);
m/z (APcI) 361 (Mϩ ϩ H, 100%).
By general procedure B, on a 1.0 mmol scale, condensation
between dianion 9 and N,N-dimethylformamide (85 µl, 1.1
mmol) gave the aldehyde 25 (0.242 g, 92%) as a colourless solid,
mp 94–95 ЊC (from ether–petrol) [Found: C, 54.90; H, 5.35; N,
21.18. C12H14N4O3 requires C, 54.94; H, 5.38; N, 21.37%]; νmax
/
cmϪ1 3257, 2981, 1748, 1700, 1596, 1496, 1394, 1370, 1257, 1159
and 1056; δH 1.49 (9H, br s, But), 7.61 (1H, dd, J 7.6 and 7.6,
5-H), 8.10 (1H, d, J 7.6, 6-H), 8.33 (1H, d, J 7.6, 4-H), 8.71 (1H,
s, NH) and 10.20 (1H, s, CHO); δC 28.4 (C(CH3)3), 84.3
(C(CH3)3), 122.5, 124.9, 127.8 (all CH), 132.0, 136.2, 146.4 (all
C), 154.2 and 189.8 (both CO); m/z 263 (Mϩ ϩ H, 100%) and
207 (52).
1-(tert-Butoxycarbonylamino)-7-(1Ј-hydroxyhexan-1Ј-yl)benzo-
triazole 27
(E)-1-(tert-Butoxycarbonylamino)-7-(2Ј-methoxycarbonylethen-
1Ј-yl)benzotriazole 31
Following general procedure B, condensation between dianion
9 (1 mmol) and hexanal (0.13 ml, 1.1 mmol) gave the alcohol 27
(0.264 g, 79%) as a colourless solid, mp 105–110 ЊC (from
Methyl triphenylphosphorane (0.73 g, 2.20 mmol) in tetra-
hydrofuran (5 ml) was added carefully to a stirred solution of
the aldehyde 25 (0.52 g, 2.0 mmol) in tetrahydrofuran (10 ml) at
2350
J. Chem. Soc., Perkin Trans. 1, 2000, 2343–2355

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ambient temperature. After 4 h, tlc analysis showed that all the
aldehyde had reacted. Ether (30 ml) was added and the resulting
suspension filtered through a pad of silica which was sub-
sequently washed with ether (2 × 20 ml). The combined filtrates
were evaporated and the residue purified by CC [petrol–ether
(7:3)] to give the (E)-unsaturated ester 31 (0.55 g, 87%) as a
colourless solid, mp 132–140 ЊC (decomp.) [Found: C, 56.75;
H, 5.97; N, 17.72. C15H18N4O4 requires C, 56.58; H, 5.70; N,
17.61%], νmax/cmϪ1 3268, 2981, 2955, 1752, 1722, 1638, 1494,
1436, 1396, 1371, 1291, 1026, 913, 804 and 732; δH 1.41–1.60
(9H, br s, But), 3.82 (3H, s, OCH3), 6.57 (1H, d, J 16.0, 2Ј-H),
7.41 (1H, dd, J 7.9 and 7.9, 5-H), 7.77 (1H, d, J 7.9, 6-H), 8.09
(1H, d, J 7.9, 4-H), 8.34 (1H, d, J 16.0, 1Ј-H) and 8.40–8.47
(1H, br s, NH); δC 28.4 (C(CH3)3), 52.3 (OCH3), 84.6 (C(CH3)3),
119.7 (C), 121.4, 122.7, 125.2, 127.0 (all CH), 130.2 (C), 137.0
(CH), 145.4 (C), 153.3 and 167.1 (both CO); m/z 319 (Mϩ ϩ H,
100%).
143.3 (both C) and 153.7 (CO); m/z 289 (Mϩ ϩ H, 100%) and
287 (65).
1-(tert-Butoxycarbonylamino)-7-(3Ј-hydroxypent-1Ј-yn-1Ј-yl)-
benzotriazole 33b
By the general procedure, coupling between iodide 30 (0.36 g,
1.0 mmol) and pent-1-yn-3-ol (130 µl, 1.5 mmol) followed by
CC [ether–petrol (1:1)] and crystallization from dichloro-
methane–petrol gave the acetylenic alcohol 33b (0.289 g, 91%)
as a pale orange solid, mp 139–143 ЊC [Found: C, 60.56; H,
6.11; N, 17.88. C16H20N4O3 requires C, 60.73; H, 6.38; N,
17.72%], νmax/cmϪ1 3397, 2962, 2926, 2110, 1724, 1667, 1435,
1258 and 1158; δH 0.90–1.05 (3 H, br res, 5Ј-CH3), 1.15–1.29
(6H, br res), 1.31–1.58 (3H, br res), 1.68–1.88 (3H, br res), 4.40–
4.76 (1H, br app d), 6.95–7.20 (1H, br app d), 7.29–7.41 (1H, br
app d), 7.79–7.89 (1H, br app d) and 9.65–9.85 (1H, br app d,
NH); δH (323 K) 1.01 (3H, br t, J ca. 6, 5Ј-CH3), 1.15–1.51 (9H,
br s, But), 1.78 (2H, br quintet, J ca. 6, 4Ј-CH2), 4.51 (1H, br res,
CHOH), 7.10 (1H, br t, J ca. 6, 5-H), 7.31 (1H, br d, J ca. 6,
6-H), 7.80 (1H, br d, J ca. 6, 4-H) and 9.27 (1H, br s, NH); δC
(323 K) 9.9 (5Ј-CH3), 28.3 (C(CH3)3), 30.8 (4Ј-CH2), 64.4 (3Ј-
CH), 78.7, 84.1, 97.1, 106.0 (all C), 121.0, 124.7, 132.3 (all CH),
132.5, 144.7 (both C) and 154.9 (CO); m/z 317 (Mϩ ϩ H,
100%).
1-(tert-Butoxycarbonylamino)-7-(2Ј-methoxycarbonylethyl)-
benzotriazole 32
The foregoing unsaturated ester 31 (0.32 g, 1.0 mmol) was
stirred in methanol (20 ml) with 10% palladium on carbon (0.05
g) under an atmosphere of hydrogen for 2 h then filtered
through a plug of Celite. The solid was washed with methanol
(2 × 10 ml) and dichloromethane (2 × 10 ml). The combined
filtrates were evaporated and the residue crystallized from
dichloromethane–petrol to give the saturated ester 32 (0.28 g,
89%) as a pale yellow solid, mp 144–145 ЊC, νmax/cmϪ1 3277,
3177, 2984, 2955, 2783, 1740, 1608, 1499, 1439, 1395, 1371,
1253, 1160, 1118, 1049, 914, 870, 803 and 754; δH 1.41–1.57
(9H, br s, But), 2.62 (2H, t, J 7.6, 2Ј-CH2), 3.31 (2H, br t, J 7.6,
1Ј-CH2), 3.60 (3H, s, OCH3), 7.26 (2H, app d, J 7.9, 5- and
6-H), 7.83 (1H, dd, J 7.9 and 1.5, 4-H) and 9.87–9.92 (1H, br s,
NH); δC 25.1 (CH2), 28.3 (C(CH3)3), 35.2 (CH2), 52.2 (OCH3),
83.8 (C(CH3)3), 118.8 (CH), 124.1 (C), 125.1, 129.2 (both CH),
133.5, 145.1 (both C), 154.4 and 173.8 (both CO); m/z
321 (Mϩ ϩ H, 100%) [Found: Mϩ ϩ H, 321.1567. C15H21N4O4
requires M, 321.1563].
1-(tert-Butoxycarbonylamino)-7-(3Ј-hydroxy-3Ј-methylbut-1Ј-
yn-1Ј-yl)benzotriazole 33c
By the general procedure, coupling between iodide 30 (1.44 g,
4.0 mmol) and 2-methylbut-3-yn-2-ol (0.58 ml, 6.0 mmol)
followed by CC [ether–petrol (1:1)] and crystallization from
dichloromethane–petrol gave the acetylenic alcohol 33c (1.10 g,
87%) as a yellow crystalline solid, mp 74–77 ЊC [Found: C,
61.04; H, 6.15; N, 17.46. C16H20N4O3 requires C, 60.73; H, 6.38;
N, 17.72%], νmax/cmϪ1 3264, 2982, 2933, 2250, 1726, 1456, 1370,
1280, 1254, 1159, 1033, 913 and 733; δH 1.25–1.37 (6H, br res,
2 × CH3), 1.37–1.75 (9H, br res, But), 4.32–4.44 (1H, br s, OH),
7.20–7.35 (1H, br res, 5-H), 7.41–7.49 (1H, br d, J ca. 8, 6-H),
7.89–7.99 (1H, br res, 4-H) and 9.05–9.15 (1H, br s, NH);
δH (330 K) 1.36–1.49 (9H, br s, But), 1.70 (1H, br s, OH), 1.71
(6H, s, 2 × CH3), 7.31 (1H, t, J 8.0, 5-H), 7.59 (1H, d, J 8.0,
6-H), 8.00 (1H, d, J 8.0, 4-H) and 8.44 (1H, br s, NH); δC (330
K) 28.3 (C(CH3)3), 31.4 (2 × CH3), 65.8 (C), 84.5 (C(CH3)3),
106.9, 120.7 (both C), 121.1, 124.7, 126.3 (all CH), 132.6, 134.8,
144.7 (all C) and 154.7 (CO); m/z 317 (Mϩ ϩ H, 100%) and 261
(22).
General conditions for Sonogashira couplings
To a stirred solution of the iodide 30 (n mmol) in degassed
tetrahydrofuran (10 ml mmolϪ1) containing triethylamine (3 ml
mmolϪ1) was added tetrakis(triphenylphosphine)palladium(0)
(20 mol%) followed by an alk-1-ynol (1.5 equivalents). The mix-
ture was further degassed by refluxing under nitrogen for 1 h
before the addition of copper() iodide (20 mol%). Refluxing
was continued for 18 h, then the mixture was cooled to ambient
temperature and treated with water (10 ml mmolϪ1). Stirring
was continued for 4 h then the mixture was separated and the
aqueous layer extracted with ether (3 × 10 ml mmolϪ1). The
combined organic solutions were washed with water (10 ml
mmolϪ1) and brine (10 ml mmolϪ1) then dried and evaporated.
The desired coupled acetylenic alcohols were then purified by
CC followed by crystallization, unless otherwise stated.
(E)-1-(tert-Butoxycarbonylamino)-7-(3Ј-phenyl-1Ј-oxoprop-2Ј-
en-1Ј-yl)benzotriazole 39 and 1-(tert-butoxycarbonylamino)-7-
(3Ј-hydroxy-3Ј-phenylprop-1Ј-yn-1Ј-yl)benzotriazole 33d
By the general Sonogashira method, coupling between iodide
30 (1.44 g, 4.0 mmol) and 1-phenylprop-2-yn-1-ol (0.792 g, 6.0
mmol) resulted in the formation of two compounds which were
separated by CC [ether–petrol (1:1)] to give i) the rearranged
enone 39 (0.76 g, 52%) as a yellow crystalline solid, mp 138–
140 ЊC (from CH2Cl2–petrol) [Found: C, 65.99; H, 5.63; N,
1-(tert-Butoxycarbonylamino)-7-(3Ј-hydroxyprop-1Ј-yn-1Ј-yl)-
benzotriazole 33a
15.63. C20H20N4O3 requires C, 65.91; H, 5.54; N, 15.38%], νmax
/
cmϪ1 3258, 2982, 1750, 1660, 1604, 1576, 1494, 1448, 1412, 1273,
1253, 1226, 1158, 1094, 1016, 772 and 697; δH 1.32–1.63 (9H, br
res, But), 7.50–7.56 (5H, m, 5 × ArH), 7.61 (1H, t, J 7.5, 5-H),
7.99 (1H, d, J 15.6, 2Ј-H), 8.18 (2H, m, 4- and 6-H), 8.21–8.30
(1H, br s, NH) and 8.92 (1H, d, J 15.6, 3Ј-H); δC 28.4 (C(CH3)3),
84.6 (C(CH3)3), 111.1 (CH), 128.4 (C), 128.5, 128.8, 129.1,
129.3, 133.5 (all CH), 133.7, 138.3 (both C), 139.2, 139.8 (both
CH), 141.3 (C), 153.2 and 191.2 (both CO); m/z (APcI) 365
(Mϩ ϩ H, 100%), 309 (99) and 265 (40); and ii) the desired
acetylenic alcohol 33d (0.55 g, 38%) as a yellow crystalline solid,
mp 78–82 ЊC (from CH2Cl2–petrol) [Found: C, 65.89; H, 5.74;
N, 15.09%], νmax/cmϪ1 3254, 3062, 2982, 2933, 2196, 1749, 1602,
By the general procedure, coupling between iodide 30 (0.36 g, 1.0
mmol) and propargyl alcohol (84 µl, 1.5 mmol) followed by CC
[ether–petrol (1:1)] and crystallization from dichloromethane–
petrol gave the acetylenic alcohol 33a (0.265 g, 92%) as a brown,
oily solid, mp 55–57 ЊC [Found: C, 58.07; H, 5.50; N, 19.57.
C14H16N4O3 requires C, 58.31; H, 5.60; N, 19.44%], νmax/cmϪ1
3282, 2974, 2933, 2360, 1744, 1456, 1370, 1278, 1254 and 1159;
δH (327 K) 1.36 (9H, br s, But), 4.55 (2H, s, 3Ј-CH2), 7.21 (1H, t,
J 8.0, 5-H), 7.42 (1H, d, J 8.0, 6-H), 7.91 (1H, d, J 8.0, 4-H) and
9.17 (1H, br s, NH); δC 26.7 (C(CH3)3), 50.2 (3Ј-CH2), 77.2,
83.3, 93.3, 104.4 (all C), 120.0, 123.5, 130.9 (all CH), 131.3,
J. Chem. Soc., Perkin Trans. 1, 2000, 2343–2355
2351

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1493, 1455, 1391, 1370, 1253, 1157, 1019, 902, 800, 741 and 699;
δH (330 K) 1.26–1.60 (9H, br s, But), 3.10–3.39 (1H, br s, OH),
5.82 (1H, s, 3Ј-H), 7.39 (2H, m, 2 × ArH), 7.46 (2H, m,
2 × ArH), 7.51 (2H, m, 2 × ArH), 7.74 (2H, m, 2 × ArH) and
8.15–8.22 (1H, br s, NH); δC (330 K) 28.4 (C(CH3)3), 65.5 (CH),
78.0, 81.6 (C), 84.6 (C(CH3)3), 109.9 (CH), 115.5, 118.0 (both
C), 127.3, 128.8, 128.9, 129.0, 129.1 (all CH), 133.2, 140.7 (both
C) and 153.1 (CO); m/z 365 (Mϩ ϩ H, 100%).
1-(tert-Butoxycarbonylamino)-7-(5Ј-hydroxypent-1Ј-yn-1Ј-yl)-
benzotriazole 36b
Iodide 30 (0.36 g, 1.0 mmol) was coupled with pent-4-yn-1-ol
(0.13 ml, 1.5 mmol) using the general procedure, followed by
CC [ether–petrol (1:1)] and crystallization from the same
solvent combination, to give the pentynol 36b (0.24 g, 76%) as
a colourless crystalline solid, mp 178–182 ЊC [Found: C, 60.88;
H, 6.15; N, 17.88. C16H20N4O3 requires C, 60.73; H, 6.38; N,
17.72%], νmax/cmϪ1 3172, 2959, 2872, 1751, 1609, 1457, 1394
and 1160; δH (333 K; d6-DMSO) 1.25–1.55 (9H br s, But), 1.56
(1H, br s, OH), 1.92 (2H, quintet, J 6.5, 4Ј-CH2), 2.66 (2H, t,
J 6.5, 3Ј-CH2), 3.91 (2H, t, J 6.5, 5Ј-CH2), 7.32 (1H, t, J 9.0,
5-H), 7.73 (1H, d, J 9.0, 6-H), 8.17 (1H, d, J 9.0, 4-H) and 8.50
(1H, s, NH); δC (323 K) 23.0 (CH2), 28.4 (C(CH3)3), 30.3, 33.4
(both CH2), 77.3, 84.0, 84.1 (all C), 118.2, 125.1 (both CH),
126.6 (C), 129.1 (CH), 131.3, 145.1 (both C) and 154.0 (CO).
1-(tert-Butoxycarbonylamino)-7-[3Ј-hydroxy-3Ј-(4-methoxy-
phenyl)prop-1Ј-yn-1Ј-yl]benzotriazole 33e
By the general Sonogashira method, coupling between iodide
30 (1.44 g, 4.0 mmol) and 1-(4-methoxyphenyl)prop-2-yn-1-ol
(0.97 g, 6.0 mmol) followed by CC [ether–petrol (1:1)] and
crystallization from CH2Cl2–petrol gave the acetylenic alcohol
33e (1.28 g, 81%) as an orange crystalline solid, mp 69–73 ЊC
[Found: C, 64.22; H, 5.60; N, 14.02. C21H22N4O4requires C,
63.93; H 5.63; N, 14.21%]; νmax/cmϪ1 3268, 2974, 1747, 1610,
1512, 1251, 1158 and 1028; δH 1.37–1.50 (9H, br s, But), 1.78
(1H, br s, OH), 3.77 (3H, s, OCH3), 5.79 (1H, s, 3Ј-H), 6.69–6.82
(2H, m, 2 × ArH), 7.33 (1H, br t, J 7.9, 5-H), 7.49 (2H, br d,
J ca. 8, 2 × ArH), 7.57 (1H, d, J 7.9, 6-H), 8.02 (1H, d, J 7.9,
4-H) and 8.95–9.15 (1H, br s, NH); δH (323 K) 1.37–1.45 (9H,
br s, But), 1.68 (1H, br s, OH), 3.81 (3H, s, OCH3), 5.70 (1H, s,
3Ј-H), 6.93 (2H, d, J 8.9, 2 × ArH), 7.35 (1H, t, J 8.0, 5-H), 7.45
(2H, d, J 8.9, 2 × ArH), 7.59 (1H, d, J 8.0, 6-H), 8.04 (1H, d,
J 8.0, 4-H) and 8.54 (1H, br s, NH); δC (330 K) 28.1 (C(CH3)3),
55.4 (OCH3), 64.7 (CH), 70.2, 80.1 (C), 84.2 (C(CH3)3), 105.7
(C), 114.2, 121.1, 124.5 (all CH), 126.5 (C), 128.2 (CH), 128.6
(C), 132.2 (CH), 132.8 (C), 144.6 (C) and 160.0 (CO); m/z 395
(Mϩ ϩ H, 22%), 377 (100) and 279 (64).
General procedure for full reduction of the acetylenic alcohols
The acetylenic alcohol 33 (1 mmol) in methanol (20 ml) was
added to 10% palladium on carbon (0.1 g) and the mixture
stirred vigorously under an atmosphere of hydrogen for
8 h then filtered through Celite. The solid was washed with
methanol (50 ml) and the combined filtrates evaporated.
General procedure for deprotection of 1-(tert-butoxycarbonyl-
amino)benzotriazoles
The 1-(tert-butoxycarbonylamino)benzotriazole [34 or 40] (n
mmol) was dissolved in dichloromethane (10 ml mmolϪ1) con-
taining trifluoroacetic acid (TFA) (2 ml mmolϪ1) and the result-
ing solution stirred at ambient temperature until tlc analysis
showed complete removal of the N-Boc group, typically 0.5–1
h. The solution was basified with 2 M aqueous sodium hydrox-
ide (~10 ml mmolϪ1), then the pH of the mixture was adjusted
to ~5 using 2 M hydrochloric acid (~3 ml mmolϪ1). The two-
phase mixture was separated and the aqueous phase saturated
with solid sodium chloride then extracted with dichloro-
methane (3 × 10 ml mmolϪ1). The combined organic solutions
were washed with brine (10 ml mmolϪ1) then dried and evapor-
ated. In most cases, the resulting 1-aminobenzotriazole was
sufficiently pure that the subsequent benzyne formation and
cyclisation were carried out immediately.
1-(tert-Butoxycarbonylamino)-7-(3Ј,4Ј-dihydroxy-3Ј-methylbut-
1Ј-yn-1Ј-yl)benzotriazole 33f
By the general procedure, coupling between iodide 30 (1.44 g,
4.0 mmol) and 2-methylbut-3-yne-1,2-diol (0.60 g, 6.0 mmol)
followed by evaporation of the cooled reaction mixture gave a
residue which was triturated with methanol (20 ml). The result-
ing mixture was filtered through Celite and the solid washed
with methanol (2 × 10 ml). The combined filtrates were dried
and evaporated and the residue crystallized from dichloro-
methane to give the acetylenic diol 33f (0.96 g, 72%) as a colour-
less crystalline solid, mp 124–128 ЊC, νmax/cmϪ1 3248, 2976,
2933, 1742, 1430, 1366, 1251, 1158 and 1044; δH (333 K) 1.23–
1.41 (9H, br s, But), 1.56 (3H s, 3Ј-CH3), 3.66 (1H, d, J 11.1,
4Ј-Ha), 3.80 (1H, d, J 11.1, 4Ј-Hb), 7.26 (1H, t, J 8.3, 5-H), 7.53
(1H, d, J 8.3, 6-H) and 8.00 (1H, d, J 8.3, 4-H); δC (330 K) 25.5
(3Ј-CH3), 28.3 (C(CH3)3), 69.8 (3Ј-C), 71.5 (4Ј-CH2), 77.7 (C),
85.7 (C(CH3)3), 98.5, 116.4 (both C), 121.4, 124.8 (both CH),
126.1 (C), 132.6 (CH), 144.8 (C) and 154.3 (CO); m/z (APcI)
333 (Mϩ ϩ H, 100%) and 259 (20) [Found: Mϩ ϩ H, 333.1567.
C16H21N4O4 requires M, 333.1563].
General procedure for benzyne generation and cyclisation
N-Iodosuccinimide (NIS) (2.5n mmol) was added in one por-
tion to a stirred solution of the 1-aminobenzotriazole (n mmol)
in dichloromethane (~30 ml mmolϪ1) at ambient temperature
and protected from light. Usually, a vigorous effervescence
occurred soon after the addition. The resulting purple solution
was stirred for 0.5 h then washed with saturated aqueous
sodium thiosulfate (5 ml mmolϪ1), water (5 ml mmolϪ1) and
brine (5 ml mmolϪ1) then dried and evaporated. CC (petrol) of
the residue then delivered the pure products. In some cases,
the NIS was added directly to the dried and filtered dichloro-
methane solution obtained from the deprotection step, without
isolation of the free amine. In such cases, a quantitative yield of
the latter was assumed when calculating the quantity of NIS to
be added.
1-(tert-Butoxycarbonylamino)-7-(4Ј-hydroxybut-1Ј-yn-1Ј-yl)-
benzotriazole 36a
Iodide 30 (0.36 g, 1.0 mmol) was coupled with but-3-yn-1-ol
(0.11 ml, 1.5 mmol) using the general procedure, followed by
CC [ether–petrol (1:1)] and crystallization from the same sol-
vent combination, to give the butynol 36a (0.24 g, 78%) as a
colourless crystalline solid, mp 168–170 ЊC [Found: C, 59.25; H,
5.78. C15H18N4O3 requires C, 59.58; H, 6.00%], νmax/cmϪ1 3278,
2980, 2249, 1724, 1608, 1456, 1254 and 1159; δH (232 K) 1.19–
1.39 (9H, br s, But), 2.70 (2H, t, J 6.0, 3Ј-CH2), 3.89 (2H,
t, J 6.0, 4Ј-CH2), 7.21 (1H, t, J 8.0, 5-H), 7.69 (1H, d, J 8.0,
6-H), 7.92 (1H, d, J 8.0, 4-H) and 9.51 (1H, br s, NH); δC (323
K) 27.9 (C(CH3)3), 35.9, 66.4 (both CH2), 82.7 (C(CH3)3),
124.5, 126.8, 133.0 (all CH) and 158.6 (CO) [other quaternaries
not observed].
1-(tert-Butoxycarbonylamino)-7-(3Ј-hydroxypropan-1Ј-yl)-
benzotriazole 34a
The acetylenic alcohol 33a (0.10 g, 0.34 mmol) was hydrogen-
ated by the general procedure to give the hydroxypropylbenzo-
triazole 34a (0.098 g, 96%) as a beige solid, mp 117–120 ЊC
[Found: C, 57.36; H, 6.96; N, 19.38. C14H20N4O3 requires C,
57.50; H, 6.90; N, 19.17%], νmax/cmϪ1 3248, 2937, 2876, 1747,
1452, 1370, 1254, 1158 and 1058; δH (330 K) 1.21–1.59 (9H, br s,
But), 1.97 (2H, br quintet, J ca. 7, 2Ј-CH2), 3.01 (2H, br t, J ca.
2352
J. Chem. Soc., Perkin Trans. 1, 2000, 2343–2355

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7, 1Ј-CH2), 3.45–3.56 (2H, br res, 3Ј-CH2), 7.15–7.29 (2H, m,
5- and 6-H), 7.81 (1H, dd, J 6.5 and 2.9, 4-H) and 9.05–9.23
(1H br s, NH); δC (330 K) 26.0 (CH2), 28.4 (C(CH3)3), 34.2, 61.7
(both CH2), 84.0 (C(CH3)3), 118.6, 125.2 (both CH), 125.3 (C),
129.5 (CH), 145.6 (C) and 154.3 (CO); m/z 293 (Mϩ ϩ H,
100%) and 237 (45).
5- and 6-H), 7.82–7.90 (1H, br res, 4-H) and 9.34–9.56 (1H, br s,
NH); δC 25.5 (2Ј-CH2), 28.5 (C(CH3)3), 29.6 (2 × CH3), 45.5
(1Ј-CH2), 71.5 (3Ј-C), 83.9 (C(CH3)3), 118.4, 125.2 (both CH),
126.4 (C), 129.1 (CH), 131.2, 145.0 (C) and 154.3 (CO); m/z 321
(Mϩ ϩ H, 100%) [Found: Mϩ ϩ H, 321.1927. C16H25N4O3
requires M, 321.1927].
8-Iodochromane 35a
2,2-Dimethyl-8-iodochromane 35c
By the general deprotection procedure followed by direct treat-
ment of the dichloromethane solution resulting from work-up
with NIS, the foregoing hydroxypropylbenzotriazole 34a (80
mg, 0.27 mmol) was converted into 8-iodochromane 35a (61 mg,
86%), a yellow solid, mp 101–102 ЊC, νmax/cmϪ1 3062, 3026,
2984, 2933, 1495, 1450, 1371, 1226, 1146, 1017, 814, 738 and
699; δH 1.90–1.97 (2H, m, 3-CH2), 2.71 (2H, app t, J 6.5,
4-CH2), 4.18–4.22 (2H, m, 2-CH2), 6.50 (1H, app t, J 7.6, 6-H),
6.92 (1H, dd, J 7.5 and 1.3, 5(7)-H) and 7.51 (1H, dd, J 8.3 and
1.2, 7(5)-H); δC 21.2, 24.2, 66.6 (all CH2), 84.4 (8-CI), 120.7
(CH), 122.2 (C), 129.0, 136.0 (both CH) and 152.6 (C); m/z (EI)
260 (Mϩ, 81%), 127 (96) and 105 (100) [Found: Mϩ, 259.9695.
C9H9IO requires M, 259.9700].
The foregoing N-Boc benzotriazole 34c (0.30 g, 0.95 mmol) was
deprotected using the general procedure to give an intermediate
amino alcohol (0.19 g, 92%) as an orange oil, νmax/cmϪ1 3341,
2074, 1674, 1373 and 1166; δH 1.24 (6H, s, 2 × CH3), 1.83–1.90
(2H, m, 2Ј-CH2), 3.19–3.24 (2H, m, 1Ј-CH2), 6.62–6.75 (2H, br
s, NH2), 7.11–7.32 (2H, m, 5- and 6-H) and 7.72 (1H, d, J 8.2,
4-H); δC 25.9 (2Ј-CH2), 29.2 (2 × CH3), 45.5 (1Ј-CH2), 73.0
(3Ј-C), 116.8, 126.5 (both CH), 127.8 (C), 129.3 (CH), 130.9
and 143.3 (both C).
Without further characterization, the foregoing amino-
alcohol (0.39 g, 1.78 mmol) was treated with NIS, as described
in the general procedure, to give the 2,2-dimethyl-8-iodo-
chromane 35c (0.45 g, 90%) as a yellow solid, mp 95–97 ЊC
[Found: C, 45.93; H, 4.76. C11H13IO requires C, 45.83; H,
4.55%], νmax/cmϪ1 3015, 2975, 2926, 2848, 1559, 1440, 1370,
1256, 1219, 1157 and 1120; δH 1.40 (6H, s, 2 × CH3), 1.83 (2H, t,
J 6.7, 3-CH2), 2.79 (2H, t, J 6.7, 4-CH2), 6.60 (1H, t, J 7.7, 6-H),
7.05 (1H, d, J 7.7, 7-H) and 7.61 (1H, d, J 7.7, 5-H); δC 23.2
(3-CH2), 27.4 (2 × CH3), 33.3 (4-CH2), 76.4 (2-C), 86.9 (8-CI),
121.6 (CH), 122.3 (C), 130.0, 137.5 (both CH) and 153.5 (C);
m/z (EI) 288 (Mϩ, 50%), 232 (53) and 127 (100) [Found: Mϩ,
288.0036. C11H13IO requires M, 288.0013].
1-Amino-7-(3Ј-hydroxypentan-1Ј-yl)benzotriazole 34b
Hydrogenation of the acetylenic alcohol 33b (0.26 g, 0.82
mmol) by the general procedure gave 1-(tert-butoxycarbonyl-
amino)-7-(3Ј-hydroxypentan-1Ј-yl)benzotriazole 34b (0.25 g,
96%) as an orange oil, δH 0.89 (3H, br t, J ca. 6, 5Ј-CH3), 1.25–
1.60 (11H, m, 4Ј-CH2 and But), 1.72 (2H, br quintet, J ca. 6, 2Ј-
CH2), 2.95–3.15 (2H, br res, 1Ј-CH2), 3.40–3.55 (1H, br res,
CHOH), 7.19–7.26 (2H br res, 5- and 6-H), and 7.72–7.86 (1H,
br res, 4-H). Without further purification or characterization,
the sample was subjected to the general deprotection procedure
to give the corresponding aminoalcohol (0.14 g, 84%) as an
orange oil, νmax/cmϪ1 3344, 2933, 2876, 1640, 1603, 1504, 1456,
1370, 1252, 1168 and 1121; δH 0.91 (3H, t, J 7.4, 5Ј-CH3), 1.51
(2H, quintet, J 7.4, 4Ј-CH2), 1.86 (2H, m, 2Ј-CH2), 2.45–2.52
(1H, br s, OH), 3.28 (2H, t, J 8.1, 1Ј-CH2), 3.51–3.57 (1H, m,
3Ј-CHOH), 6.12 (2H, br s, NH2), 7.11–7.23 (2H, m, 5- and 6-H)
and 7.76–7.82 (1H, m, 4-H); δC 8.9 (5Ј-CH3), 25.4, 29.2, 37.7
(all CH2), 71.1 (3Ј-CH), 116.3, 123.4 (both CH), 125.6 (C),
127.0 (CH), 131.0 and 143.9 (both C); m/z 221 (Mϩ ϩ H, 100%)
[Found: Mϩ ϩ H, 221.1404. C11H17N4O requires M, 221.1402].
1-(tert-Butoxycarbonylamino)-7-(3Ј,4Ј-dihydroxy-3Ј-methyl-
butan-1Ј-yl)benzotriazole 34f
Benzotriazole 33f (0.24 g, 0.72 mmol) was hydrogenated using
the general procedure to give the diol 34f (0.22 g, 92%) as a
colourless solid, mp 132–135 ЊC [Found: C, 55.54; H, 6.94; N,
16.28. C16H24N4O4 requires C, 57.11; H, 7.19; N, 16.66%], νmax
/
cmϪ1 3350, 2979, 1740, 1440, 1376, 1255, 1159 and 773; δH (333
K) 1.30 (3H, s, 3Ј-CH3), 1.50 (9H, s, But), 1.83–1.90 (2H, m,
2Ј-CH2), 3.04–3.11 (2H, m, 1Ј-CH2), 3.52 (1H, d, J 10.9, 4Ј-Ha),
3.60 (1H, d, J 10.9, 4Ј-Hb), 7.32 (2H, m, 5- and 5-H) and 7.89–
7.96 (1H, m, 4-H); m/z 337 (Mϩ ϩ H, 100%) and 279 (57)
[Found: Mϩ ϩ H, 337.1876. C16H25N4O4 requires M, 337.1876].
2-Ethyl-8-iodochromane 35b
(8-Iodo-2-methylchroman-2-yl)methanol 35f
The foregoing 1-aminobenzotriazole, derived from benzo-
triazole 34b (0.36 g, 1.63 mmol) was treated with NIS, as
described in the general procedure, to give the 2-ethyliodo-
chromane 35b (0.40 g, 85%) as a yellow solid, mp 107–109 ЊC;
νmax/cmϪ1 2955, 2923, 2848, 1638, 1449, 1373, 1237, 1108, 1072
and 757; δH 0.98 (3H, t, J 6.0, CH3CH2), 1.72–1.89 (3H, m, 3-Ha
and CH3CH2), 2.01 (1H, dddd, J 13.6, 8.6, 5.4 and 2.6, 3-Hb),
2.73 (1H, dd, J 16.6, 5.5 and 5.4, 4-Ha), 2.85 (1H, ddd, J 16.6,
11.0 and 5.5, 4-Hb), 3.99 (1H, dddd, J 10.2, 7.7, 2.6 and 2.5,
2-H), 6.58 (1H, t, J 7.7, 6-H), 7.00 (1H, d, J 7.7, 7-H) and 7.56
(1H, d, J 7.7, 5-H); δC 10.4 (CH3), 25.4, 27.5, 28.7 (all CH2),
78.9 (2-CH), 86.4 (8-CI), 121.9 (CH), 123.2 (C), 130.0, 137.3
(both CH) and 152.3 (C); m/z (EI) 288 (Mϩ, 100%) and 233 (80)
[Found: Mϩ, 288.0011. C11H13IO requires M, 288.0013].
By the combined deprotection and cyclisation procedures in
which the intermediate 1-aminobenzotriazole was not isolated,
the foregoing diol 34f (0.354 g, 1.05 mmol) was converted into
the 8-iodochromanylmethanol 35f (0.25 g, 78%) as a beige oil,
νmax/cmϪ1 3418, 2955, 2931, 2924, 1442, 1374, 1238, 1153, 1054
and 763; δH 1.37 (3H, s, 2-CH3), 1.75 (1H, ddd, J 13.7, 6.2 and
4.2, 3-Ha), 1.97 (1H, ddd, J 13.7, 11.1 and 6.0, 3-Hb), 2.77 (1H,
ddd, J 16.6, 6.2 and 6.0, 4-Ha), 2.86 (1H, ddd, J 16.6, 11.1 and
4.2, 4-Hb), 3.61 (1H, d, JAB 9.7, 1Ј-Ha), 3.64 (1H, d, JAB 9.7,
1Ј-Hb), 6.64 (1H, t, J 7.7, 6-H), 7.11 (1H, d, J 7.7, 7-H) and 7.64
(1H, d, J 7.7, 5-H); δC 21.1 (2-CH3), 22.1, 28.3 (3- and 4-CH2),
69.7 (CH2OH), 79.0 (2-C), 86.8 (8-CI), 122.2 (CH), 122.9 (C),
130.0, 137.4 (both CH) and 152.4 (C); m/z (EI) 304 (Mϩ, 42%),
273 (84), 146 (36), 131 (61), 105 (93) and 77 (100) [Found:
Mϩ, 303.9951. C11H13IO2 requires M, 303.9962].
1-(tert-Butoxycarbonylamino)-7-(3Ј-hydroxy-3Ј-methylbutan-1Ј-
yl)benzotriazole 34c
(Z)-1-(tert-Butoxycarbonylamino)-7-(3Ј-hydroxyprop-1Ј-en-1Ј-
yl)benzotriazole 40a
The acetylenic alcohol 33c (0.54 g, 1.71 mmol), derived from
2-methylbut-3-yn-2-ol, was subjected to the general hydrogen-
ation procedure to give the 3Ј-hydroxybutylbenzotriazole 34c
(0.52 g, 95%) as an orange oil, νmax/cmϪ1 3288, 2973, 1748, 1459,
1370, 1276, 1254, 1159 and 773; δH 1.27–1.34 (6H, app br s,
2 × CH3), 1.35–1.61 (9H, br s, But), 1.79–1.82 (2H, br res,
2Ј-CH2), 3.06–3.15 (2H, br res, 1Ј-CH2), 7.25–7.32 (2H, br res,
Benzotriazole 33a (0.10 g, 0.34 mmol), derived from propar-
gylic alcohol, in methanol (1 ml) was added to a suspension of
10% palladium on charcoal (0.05 g) in methanol (5 ml) contain-
ing quinoline (10 µl). The resulting mixture was stirred vigor-
ously under an atmosphere of hydrogen for 2 h, then the
J. Chem. Soc., Perkin Trans. 1, 2000, 2343–2355
2353

View Article Online
methanol was evaporated and the resulting residue taken up in
dichloromethane (10 ml). The resulting mixture was filtered
through Celite and the solid washed with dichloromethane (20
ml). The combined filtrates were washed with 2 M hydrochloric
acid (2 ml) then dried and evaporated to give the crude (Z)-
allylic alcohol 40a (0.10 g, ~100%), νmax/cmϪ1 3368, 1718, 1370,
1026 and 909; δH (323 K) 1.26–1.50 (9H, br s, But), 4.09 (2H, d,
J 7.0, CH2OH), 4.46 (1H, s, OH), 6.05 (1H, m, 2Ј-H), 6.81 (1H,
br d, J 12.0, 1Ј-H), 7.13 (1H, d, J 8.0, 6-H), 7.27 (1H, t, J 8.0,
5-H), 7.83 (1H, d, J 8.0, 4-H) and 9.48 (1H, s, NH); δC (232 K)
26.2 (C(CH3)3), 61.6 (CH2), 83.6 (C(CH3)3), 119.4 (CH), 120.6
(C), 124.9, 125.2, 129.6 (all CH), 130.5 (C), 134.4 (CH), 144.7
(C) and 154.5 (CO).
cmϪ1 2962, 2926, 2869, 1588, 1437, 1380, 1223, 1122, 1058, 901,
865 and 786; δH 1.19 (3H, t, J 9.6, 2Ј-CH3), 1.53–1.62 (2H, m,
1Ј-CH2), 4.82 (1H, br td, J 8.1 and 3.5, 2-H), 5.63 (1H, dd, J 9.7
and 3.5, 3-H), 6.24 (1H, dd, J 9.7 and 1.5, 4-H), 6.54 (1H, t,
J 7.7, 6-H), 6.84 (1H, dd, J 7.7, 5-H) and 7.45 (1H, dd, J 7.7,
7-H); δC 8.6 (2Ј-CH3), 27.5 (1Ј-CH2), 59.8 (2-CH), 83.6 (8-CI),
121.6, 122.5 (CH), 124.2 (C), 124.9, 127.2, 137.0 (all CH) and
153.0 (C) [Found: Mϩ ϩ H, 286.9932. C11H12IO requires M,
286.9935].
(Z)-1-(tert-Butoxycarbonylamino)-7-(3Ј-hydroxy-3Ј-methylbut-
1Ј-en-1Ј-yl)benzotriazole 40c
Benzotriazole 33c (0.316 g, 1.0 mmol), derived from 2-methyl-
but-3-yn-2-ol, was reduced using Rieke zinc according to the
general procedure to give the corresponding (Z)-allylic alcohol
40c (0.254 g, 80%) as an oil, νmax/cmϪ1 3342, 2976, 2912, 1738,
1573 and 1152; δH (330 K) 1.28 (6H, s, 2 × CH3), 1.54 (9H, s,
But), 5.98 (1H, d, J 12.4, 2Ј-H), 6.57 (1H, d, J 12.4, 1Ј-H), 7.29–
7.35 (2H, m, 5- and 6-H), 7.89 (1H, dd, J 6.4 and 2.1, 4-H) and
8.99 (1H, s, NH); m/z 319 (Mϩ ϩ H, 100%).
8-Iodochromene 41a
Deprotection and cyclisation, using TFA and NIS respectively,
of the foregoing (Z)-allylic alcohol 40a (100 mg, 0.34 mmol)
according to the general procedures gave the 8-iodochromene
41a (70 mg, 75% overall) as a brown oil, νmax/cmϪ1 3048, 2960,
2926, 2848, 1441, 1224, 1170, 1072, 1014, 929, 889, 790 and 688;
δH 4.97 (2H, dd, J 3.5 and 1.9, 2-CH2), 5.79 (1H, dt, J 9.8 and
3.5, 3-H), 6.37 (1H, dt, J 9.8 and 1.9, 4-H), 6.65 (1H, t, J 7.8,
6-H), 6.92 (1H, dd, J 7.8 and 1.3, 5-H) and 7.56 (1H, dd, J 7.8
and 1.3, 7-H); δC 67.0 (2-CH2), 84.2 (8-CI), 122.9 (CH), 123.3
(C), 123.4, 124.7, 127.1, 138.9 (all CH) and 153.7 (C); m/z (EI)
258 (Mϩ, 54%), 127 (97) and 89 (100) [Found (EI): Mϩ,
257.9543. C9H7IO requires M, 257.9543].
(8-Iodo-2-methylchromen-2-yl)methanol 41d
Benzotriazole 33f (0.33 g, 1.0 mmol), derived from 2-methylbut-
3-yne-1,2-diol, was reduced using Rieke zinc according to the
general procedure to give the corresponding (Z)-allylic alcohol
40d (0.20 g, 60%) as an oil, νmax/cmϪ1 3376, 2962, 2920, 2855,
1732, 1459, 1370, 1257, 1159, 1051 and 650; δH (330 K) 1.27–
1.34 (9H, br s, But), 1.40–1.48 (3H, br s, 3Ј-CH3), 3.30 (1H, br d,
J 10.7, 4Ј-Ha), 3.39 (1H, br d, J 10.7, 4Ј-Hb), 5.82 (1H, br d,
J 12.3, 2Ј-H), 6.57 (1H, br d, J 12.3, 1Ј-H), 7.30–7.35 (2H, m,
5- and 6-H), 7.66–7.69 (1H, br res, 4-H) and 9.51–9.55 (1H, br s,
NH).
A sample of the foregoing allylic alcohol 40d (0.158 g, 0.24
mmol) was immediately subjected to the combined depro-
tection–cyclisation procedure by sequential treatment with
TFA and NIS to give the iodochromen-2-ylmethanol 41d (0.091
g, 63%) as a yellow oil, νmax/cmϪ1 3259, 2955, 2855, 1459, 1430,
1258, 1087, 1051 and 793; δH 1.34 (3H, s, 2-CH3), 3.60 (2H, s,
2-CH2OH), 5.51 (1H, d, J 9.8, 3-H), 6.30 (1H, d, J 9.8, 4-H),
6.59 (1H, t, J 7.6, 6-H), 6.92 (1H, dd, J 7.6, and 1.3, 5-H) and
7.48 (1H, dd, J 7.6 and 1.3, 7-H); δC 21.4 (2-CH3), 59.0
(2-CH2OH), 79.6 (2-C), 87.2 (8-CI), 120.1 (CH), 122.3 (C),
125.2, 126.2, 128.4, 137.1 (all CH) and 152.3 (C) [Found (EI):
Mϩ, 301.9807. C11H11IO2 requires M, 301.9806].
Formation and use of Rieke zinc24
Clean potassium (0.078 g, 2 mmol) was added to a still suspen-
sion of anhydrous zinc chloride (0.276 g, 2 mmol) in dry tetra-
hydrofuran (20 ml). After the initial reaction subsided, the
mixture was stirred slowly then gradually heated to reflux. The
resulting jet-black suspension was refluxed for 2 h then a solu-
tion of a propargyl alcohol (1 mmol) in methanol (15 ml) was
added dropwise, followed by water (3 ml). Refluxing was con-
tinued, with protection from light, for 16 h, then the suspension
was cooled to ambient temperature and filtered through Celite.
The reaction vessel and solids were rinsed with ether (30 ml)
and the combined filtrates separated. The aqueous layer was
acidified with 2 M hydrochloric acid and saturated with solid
sodium chloride before being extracted with ether (2 × 20 ml).
The combined organic solutions were washed with brine (30 ml)
then dried and evaporated to give the (Z)-allylic alcohol, suf-
ficiently pure for use in the final deprotection–cyclisation steps.
Acknowledgements
(Z)-1-(tert-Butoxycarbonylamino)-7-(3Ј-hydroxypent-1Ј-en-1Ј-
We are very grateful to Dr R. S. Ward (Swansea) and Dr R. C.
D. Brown (Southampton) for helpful suggestions regarding
the alkyne reduction step, to the EPSRC Mass Spectrometry
Service, University College, Swansea for the provision of high
resolution mass spectral data, to Mr Stanley K. Y. Li and Miss
Kathy N. Price for some preliminary experiments, to Robert
Jenkins for the provision of spectra data, and to Cardiff
University for financial support. This paper is dedicated to the
memory of Leslie Crombie, an outstanding chemist, teacher
and wise mentor.
yl)benzotriazole 40b
Reduction of the acetylenic alcohol 33b (0.316 g, 1.0 mmol)
using Rieke zinc by the general procedure gave the (Z)-allylic
alcohol 40b (0.305 g, 94%) as a yellow oil, νmax/cmϪ1 3380, 1725,
1380, 1029 and 910; δH (333 K) 0.85 (3H, t, J 6.4, 5Ј-CH3), 1.42–
1.54 (9H, br s, But), 1.55–1.60 (2H, m, 4Ј-CH2), 4.03 (1H, m,
3Ј-CHOH), 4.42–4.49 (1H, br s, OH), 5.89 (1H, dd, J 11.2 and
9.5, 2Ј-H), 6.81 (1H, br d, J 11.2, 1Ј-H), 7.24 (1H d, J 7.1, 6-H),
7.32 (1H, t, J 7.1, 5-H) and 7.89 (1H, d, J 7.1, 4-H); δC (330 K)
10.0 (5Ј-CH3), 28.6 (C(CH3)3), 30.1 (4Ј-CH2), 69.6 (3Ј-CH), 83.6
(C(CH3)3), 119.6 (CH), 120.8 (C), 124.9, 128.4, 129.5 (all CH),
130.7 (C), 138.0 (CH), 144.9 (C) and 154.5 (CO); m/z 333
(Mϩ ϩ H, 100%) and 259 (20) [Found: Mϩ ϩ H, 315.1459.
C16H19N4O3 requires M, 315.1457].
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