The scope and limitations of deuteration mediated by Crabtree's catalyst

Article abstract of DOI:10.1016/S0040-4020(01)00945-0

Exchange of protons for deuterons mediated by Crabtree's catalyst, 1, is directed efficiently by a functional group containing an sp²-hybridised nitrogen or oxygen atom; more electron-rich substrates are, in general, deuterated more efficiently. The electronic effects of substituents in the arene ring are critical only where the directing group is poor, in which case exchange is generally promoted by electron donating substituents, but the exchange is impeded by bulky meta-substituents.

Full text of DOI:10.1016/S0040-4020(01)00945-0

TETRAHEDRON
Pergamon
Tetrahedron 57 32001) 9487±9497
The scope and limitations of deuteration mediated by
Crabtree's catalyst
George J. Ellames, Jennifer S. Gibson, John M. Herbertp and Alan H. McNeill
Â
Isotope Chemistry and Metabolite Synthesis Department, Sano®-Synthelabo, Willowburn Ave., Alnwick, Northumberland NE66 2JH, UK
Received 2 July 2001; revised 29 August 2001; accepted 20 September 2001
AbstractÐExchange of protons for deuterons mediated by Crabtree's catalyst, 1, is directed ef®ciently by a functional group containing an
sp2-hybridised nitrogen or oxygen atom; more electron-rich substrates are, in general, deuterated more ef®ciently. The electronic effects of
substituents in the arene ring are critical only where the directing group is poor, in which case exchange is generally promoted by electron
donating substituents, but the exchange is impeded by bulky meta-substituents. q 2001 Elsevier Science Ltd. All rights reserved.
Over the past decade, a number of reports have appeared
describing the use of iridium complexes to promote the
incorporation of tritium and deuterium into arenes at
positions ortho- to a directing group such as a carbonyl.1±4
The isotopic hydrogen is thereby incorporated at a position
where it is not particularly susceptible toward loss by
metabolism or uncatalysed exchange. One of the more
attractive pre-catalysts of this process, by virtue of its
stability and commercial availability, is Crabtree's catalyst
[3cyclooctadiene)3pyridine)3tricyclohexylphosphine)iridium3I)
hexa¯uorophosphate, 1]. Since the published deuteration
work involving this catalyst is limited to a few examples
only,2,3 we chose to carry out a more extensive investigation
of the range of substrates for which the process might be
useful.
approach was intended to overcome any poisoning of the cata-
lyst that might result from irreversible binding to the substrate.
Moreover, it has been found that the binding modes of some
ligands with iridium species are dependant upon the ligand/
metal ratio,4 and so we wished to keep this ratio constant.
Nevertheless, it was of interest to check whether this did,
indeed, correspond to an optimum catalyst/substrate ratio
3Fig. 1). Using ethyl benzoate, the highest level of deuterium
incorporationisobservedusinga1:2ratioof1tosubstrate,and
the extent of deuteration is much reduced with greater quan-
tities of 1. By comparison, complete deuteration of 1-phenyl-
pyrazoleisobservedinthepresenceofaslittleas25% 1, above
which increasing the concentration of 1 has no effect. It is
therefore likely that many of the ®gures presented below
could be bettered slightly by using a smaller quantity of cata-
lyst. Multiple runs were conducted in a few cases only, but
reproducibility in these cases appears to be within 5±10%,
which is suf®cient to derive general trends. Since a weakly
coordinating ligand is believed to be involved at several criti-
cal stages of the exchange process,1,5 we chose to add a trace
quantity of deuterium oxide to each exchange mixture. The
anticipated exchange process should therefore be as illustrated
in Scheme 1.
Upon examining the deuteration of a range of aromatic
esters, amides, and ketones mediated by 1, a number of
trends are clear 3Table 1). The deuteration of amides
mediated by 1 has been reported previously,2 and indeed
this proves to be a comparatively ef®cient process. Not
surprisingly, the process with amides is more ef®cient
than that with esters; this appears to be principally an elec-
tronic effect associated with the electron-donating ability of
the coordinating substituent, and is substantially unaffected
by increasing steric demand at the amide nitrogen. This
indicates that in amides it is still the oxygen that coordinates
to the metal centre. Indeed, N,N-diisopropylbenzamide is
essentially as good a substrate as N,N-dimethylbenzamide,
1. Results and discussion
Since deuterium and tritium should behave similarly in
exchange processes, our investigations were carried out with
the former for reasons of convenience. In order to maintain
comparable conditions throughout the investigation, 1 was
used in stoichiometric or near-stoichiometric quantities. This
Keywords: iridium complexes; deuterium exchange; isotope exchange.
Corresponding author; e-mail: john.herbert@sano®-synthelabo.com
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020301)00 945-0

9488
G. J. Ellames et al. / Tetrahedron 57 .2001) 9487±9497
Figure 1. Variation of deuterium incorporation into ethyl benzoate and 1-phenylpyrazole with substrate/catalyst.
and both are superior to benzamide itself. The degree of
deuteration of amides appears to be substantially unaffected
by the electronic effect of substituents in the arene ring, the
behaviour of N,N-dimethyl-4-methoxy and 4-nitrobenza-
mides being identical to that of the ring-unsubstituted
species. On the other hand, electronically different ethyl
benzoates give signi®cantly differing results: the process
is clearly impeded by a para-nitro group and assisted very
slightly by a para-methoxy group. It may be inferred that
the coordinating power of the ester is substantially improved
by the presence of an electron donating substituent, leading
to better deuterium incorporation; conversely, the electron-
withdrawing nitro group reduces the coordinating ability of
the ester, and so the level of deuteration is reduced.
It is to be expected that an ortho-substituent would block
Scheme 1. Simpli®ed mechanism of the exchange process n the presence of deuterium oxide.

G. J. Ellames et al. / Tetrahedron 57 .2001) 9487±9497
Table 1. Deuteration of ketone and acid derivatives mediated by 1
9489
Entry
X
Y
R
Equiv. 1
o-Da
Notes
1
2
3
4
5
6
7
8
O
O
O
O
O
O
O
O
O
OEt
OEt
OEt
OEt
OMe
OMe
OMe
NH2
H
1.01.6
1.3
1.2
1.010:1 C-2/C-4
0.6
1.00
0.7
1.1
1.1
4-OMe
4-NO2
3-aza
2-Br
2-COOMe.1
3-COOMe
H
1.7
0.4
.8
0.1
No methyl benzoate detected
No deuteration at position 2.
1.1
1.3
9
NMe2
H
1.6
10O
11
12
13
15
16
17
18
19
20O
21
22
23
24
25
26
27
NMe
4-OMe
4-NO2
3-F
3-OMe
3-Cl
3-Br
3-CF3
H
H
1.01.6
1.01.6
1.01.9
1.011.8.0D in
1.01.3.3D in
1.0N1o.0D in
1.01.7.3D in
1.01.2.8D in
1.01.5
1.1D in
No D in
No D in
N-Me
N-Me
N-Me
N-Me; C6/C2ˆ9:1.
N-Me; C6/C2ˆ8:5.
N-Me; C6/C2ˆ8:2.
N-Me; C6/C2ˆ9:4.
N-i-Pr
2
O
O
O
O
O
O
O
O
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
N-i-Pr2
Me
0
0
0
Me
4-OMe
.9
4-NO2
H
1.0 0
O
O
Me
Ph
Me
Me
Me
1.1
1.4
3.4
1.6
1.5
NOMe
NNMe2
NNHPh
NH
H
4-NO2
4-NO2
H
1.1
1.5D in N-Me
N-Ph
1.01.4
1.00
1.0±
1.3D in
NHCOOEt
SMe
.4
S
H
Substrate degraded
a
Figures presented are the average number of ortho-deuterium atoms incorporated per molecule.
deuteration, but it was of interest to ascertain whether the
method would tolerate an ortho-halogen which, indeed, it
does 3Table 1, entry 5). However, the presence of even a
relatively small meta-substituent substantially reduces the
degree of deuteration at the adjacent 2-position: in the
absence of any effect of a para-subsituent upon the deutera-
tion of dimethylbenzamides, it appears that this is a steric
effect. This is underlined by the comparative ef®ciency of
deuteration of N,N-dimethyl-3-¯uorobenzamide, whereas
3-bromo, 3-chloro, and 3-tri¯uoromethyl substituents
3Table 1, entries 12±17) all impede the exchange process
to at least some extent, with exchange in these substrates
occurring principally at the 6-position.
the adjacent nitrogen would require formation of a three-
membered metallacycle, it seems likely that this exchange
occurs via coordination to the oxygen, as for the arene
deuteration, and intermediacy of a 5-membered metalla-
cycle such as 2. Deuteration at a saturated carbon was not
observed with ketones or esters, and although it is not
restricted to amides 3Table 1, entry 24), aliphatic deutera-
tion has only been observed, so far, adjacent to nitrogen. We
are presently investigating the scope of this exchange
process.
Aryl ketones appear to be good substrates for the exchange
process, with benzophenone and acetophenone incorporat-
ing deuterium at similar levels to N,N-dimethylbenzamide.
Oddly, the presence of a para-methoxy group reduces the
degree of deuteration of acetophenone, but a para-nitro
group has little effect; this may re¯ect the existence of alter-
native deuteration pathways as has been suggested
previously.1 Given that amides are generally better
substrates than esters, it was expected that oximes, hydra-
zones, or amidines would prove to be better deuteration
substrates than their oxygen analogues. Nevertheless, the
O-methyloxime and hydrazones formed from acetophenone
incorporated deuterium to essentially the same extent as the
ketone. Benzamidine was completely degraded within one
hour in the presence of 1 and deuterium, apparently to
benzonitrile, although the latter was not isolated, but
characterised only by GC/MS; N-ethoxycarbonylbenz-
amidine 3Table 1, entry 26) was a poor substrate. Methyl
dithiobenzoate was also expected to be a good exchange
Incorporation of deuterium a- to the nitrogen of an N,N-
dialkylamide is a common phenomenon. Since direction by

9490
G. J. Ellames et al. / Tetrahedron 57 .2001) 9487±9497
Table 2. Deuteration of indole-2-carboxamides mediated by 1
Entry
R1/R2
Equiv. 1
3-Da
Notes
1
2
3
4
Me/Ph
Me/OMe
Me/Bn
H/Bu
0.5
1.1
1.2
1.1
0.7
0.3
0.7
0.1
No deuteration in Ph
.50% degradation
a
Figures presented are the average number of ortho-deuterium atoms incorporated per molecule.
Table 3. Deuteration of 1-indanone, tetralone, and benzosuberone mediated
by 1
suffered slow degradation under the exchange conditions:
this did not appear to be due to reduction to the aldehyde,
unless the latter was itself degraded further.
It appears that metallacycle formation from indole-2-
carboxamides is less favoured than from benzamides,
since a C3±H bond is less well placed to permit an agostic
interaction with the metal centre. This supposition was
tested further by examination of the deuteration of
1-indanone, 1-tetralone, and 1-benzosuberone, which repre-
sent a series of electronically very similar substrates, where
the geometry of the carbonyl oxygen is constrained by ring
formation, and which therefore differ principally in the
distance between the directing heteroatom and the C±H
bond into which iridium must insert in order to form a
metallacycle. In this case 3Table 3), there is a clear trend
such that 1-indanone is the worst, and benzosuberone the
best substrate. It is clear, and scarcely surprising, that
increasing the distance between the directing heteroatom
and the site of C±H insertion results in a reduction in
deuteration. Consistent with this trend, deuterium incor-
poration was not observed using either phenylacetone 33)
or benzylacetone 34).
Entry
Substrate
n
Equiv. 1
7/8/9-Da
1
2
3
1-Indanone
1-Tetralone
1-Benzosuberone
01..031
1.68
2.76
0
1.00
1.00
a
Figures presented are the average number of ortho-deuterium atoms
incorporated per molecule.
substrate, but did not survive the deuteration conditions
3Table 1, entry 27).
Deuteration at the 3-position of indole-2-carboxamides was
signi®cantly less ef®cient than ortho-deuteration of benz-
amides 3Table 2). That the observed deuterations are
iridium-mediated, rather than the consequence of electro-
philic protonation 3vide infra), was demonstrated by the
absence of deuterium incorporation, other than at nitrogen,
upon treatment of N-methyl-N-phenylindole-2-carboxamide
with deuterium oxide. The Weinreb amide 3Table 2, entry 2)
Many compounds whose deuterated and tritiated derivatives
would be of value in pharmaceutical development contain
Table 4. Deuteration of aniline, phenol, and thiophenol derivatives mediated by 1
Entry
Z
R
Equiv. 1
o-Da
1
2
3
4
5
6
7
8
OH
OAc
NH2
NHAc
NHBoc
NHSO2Me
NHTs
NMs2
H
H
H
H
2-i-Pr
H
.0
.0
.0
1.00
1.00
1.00
1.4
1.1
1.1
0.9
1.2
0.8
0.5
0.3
0.0
0.0
4-Cl
H
9
NHNH2
H
3isolated a1s.0a1n.i0line)
10NHN
11
12
13
14
vC3Me)-p-C6H4NO2
H
1.01.3
1.00
1.00
1.00
1.00
NO2
H
H
H
H
.0
S3O)Me
SO2Me
SO2NH2
.1
.0
.3
a
Figures presented are the average number of ortho-deuterium atoms incorporated per molecule.

G. J. Ellames et al. / Tetrahedron 57 .2001) 9487±9497
9491
Table 5. Deuteration and N±N cleavage of phenylhydrazine mediated by different percentages of 1
Entry
Equiv. 1
Time 3h)
Hydrazine/anilinea
o-D in hydrazineb
o-D in anilineb
1
2
3
4
1.1
1.0
0.5
0.1
24
15
15
15
0:100
0:100
13:87
61:39
±
±
1.4
1.5
1.0
1.5
1.3
0.5
a
Ratio from GC/MS.
Figures presented are the average number of ortho-deuterium atoms incorporated per molecule.
b
arenes bound directly to heteroatoms. The deuteration of a
range of model substrates of this type by 1 was therefore
examined 3Table 4). In practice, few of these substrates
were deuterated at all, let alone ef®ciently; the deuteration
and tritiation of acetanilide and related substrates,
apparently via a six-membered metallacycle, has been
reported previously.2 We were able to reproduce the
deuteration of acetanilide, and of a related tert-butyl-
carbamate 3Table 4, entries 4 and 5), although the degree
of deuteration was modest, in line with the poor
results obtained with phenylacetone. In the case of
N-phenylmethanesulfonamide 3Table 4, entry 6), the
coordinating atom could, in principle, be either nitrogen
or oxygen; the possibility that deuteration might occur via
a four-membered metallacycle is suggested by the ef®cient
exchange observed with benzosuberone 3Table 3, entry 3).
However, the absence of deuteration of aniline or phenol
does not support this idea.
exchange, and therefore that it might be possible to recover
deuterated phenylhydrazine by carrying out the exchange
using a smaller quantity of 1. Indeed 3Table 5), this did
prove to be the case and it is no surprise that, with the
rate of N±N cleavage slowed, the deuterium incorporation
improved also. Phenylhydrazine therefore represents a
convenient synthon for aniline in this process.6
Ef®cient deuterium exchange was observed with a variety of
aryl-substituted heterocycles 3Table 6), the nature of the
directing heteroatom being critical. Where deuteration is
directed by an sp2 nitrogen, irrespective of whether the
heterocycle is p-excessive or p-de®cient, deuterium
incorporation is ef®cient in most cases. In contrast, direction
by an oxygen, sulfur, or sp3 nitrogen is consistently poor.
These observations are consistent with a process whereby
initial coordination occurs via the lone pair of the directing
heteroatom; where this is coplanar with the arene ring,
agostic interaction and subsequent C±H activation will be
more favoured than where the directing heteroatom has lone
pairs out of the plane of the arene system. This contrast is
readily observed in the case of isomeric phenylthiazoles
3Table 6, entries 5±7), where direction by nitrogen is
ef®cient but direction by sulfur is poor. In these substrates,
increasing the electron density of the heterocycle by
amination 3Table 6, entry 8) results in a further increase in
The best substrates in this group were phenylhydrazine
3Table 4, entry 9) and, less surprisingly, the phenyl-
hydrazone of 4-nitroacetophenone 3Table 4, entry 10). In
the former case, N±N cleavage is observed also, but it is
almost certain that phenylhydrazine is the deuteration
substrate since deuteration of aniline itself is not observed.
It follows that N±N cleavage is slower than deuterium
Table 6. Deuteration of aryl heterocycles mediated by 1
Entry
Heterocycle
R2
Equiv. 1
o-Da
Notes
1
2
2-Furyl
2-Thienyl
4-OMe
4-OMe
1.1
1.0
0.4
0.1
0.7D at furan C-2
0.7D at thiophene C-2
3
4
5
3,3-Dimethyloxazolin-2-yl
5-Acetyl-isoxazol-3-yl
Thiazol-2-yl
2-OMe.5
H
H
1.00
1.02.0
1.01.6D at thiazole 1C.-04
6
7
Thiazol-4-yl
Thiazol-5-yl
H
H
1.1
1.0
1.6
0.2
1.0D at thiazole C-2
0.4D at thiazole C-2
8
9
2-Aminothiazol-4-yl
2-Benzamidothiazol-4-yl
Imidazol-4-yl
Pyrazol-1-yl
Pyrazol-3-yl
1-Methylpyrazol-3-yl
1-Methylpyrazol-5-yl
2-Benzoyltetrazol-5-yl
2-Benzyltetrazol-5-yl
2-Pyridinyl
H
H
H
H
4-Cl
1.1
1.1
0.5
1.02.0
0.6
1.01.7
1.00
0.8
.6D at th2ia.0zo0le C-5
0.6
1.8
0.4D in benzoyl group
0.4D at imidazole C-2
10
11
12
13
14
15
16
17
18
19
0.6
Partially degrades
1.7D in benzoyl
4-Cl
4-Cl .6
H
H
H
H
H
1.9
2.0
1.1
1.01.6.6D at pyridine0C-2.
1.5
Pyrazinyl
4-Pyrimidinyl
0.9
1.01.7
Similar incorporation occurs with D2O alone.
Figures presented are the average number of ortho-deuterium atoms incorporated per molecule.
a

9492
G. J. Ellames et al. / Tetrahedron 57 .2001) 9487±9497
Scheme 2. Uncatalysed deuterium exchange in 2-aminothiazoles.
deuterium incorporation, which is more than reversed when
the amine is acylated 3Table 6, entry 9). The isomeric
pyrazoles 3Table 6, entries 13 and 14) display a similar
pattern. In view of the apparent ef®cacy of an sp2-hybridised
nitrogen as a coordinating centre, it was of interest to
examine the deuteration of arylazines. From the few
examples given, it can be seen that these are also good
deuteration substrates.
well. In most cases, the same exchange is not observed in
the presence of deuterium oxide or deuterium chloride
alone, indicating that it is iridium-mediated. H5 in
2-aminothiazoles, however, is exchanged by deuterium
oxide alone although the exchange is suppressed by
acylation of the amine; this exchange may be rationalised
as illustrated in Scheme 2.
By way of contrast, H2 in 4- or 5-phenylthiazoles and H4 in
2-phenylthiazole are exchanged in the presence of 1, but not
with deuterium oxide alone; indeed, deuteration at C2 in
thiazoles normally requires deprotonation by an alkyl-
lithium base.8 In the same manner, treatment of thiazole
or benzothiazole with deuterium in the presence of 1 3one
equivalent) also results in exchange at C2 327 and 45%,
respectively). Deuterium is also incorporated into the pyri-
dine ring of 2-phenylpyridine. Since in all cases deuterium
is incorporated adjacent to a pyridine-like nitrogen, and that
1 is known to mediate both the hydrogenation of imines9 and
the dehydrogenation of cyclohexenes to arenes,10 it is
possible that this exchange proceeds by means of a rever-
sible partial hydrogenation of the heterocycle 3Scheme 3).
It is of interest also to note that deuterium incorporation is
facilitated more by heteroarenes, rather than their partially
hydrogenated analogues 3Table 6, entry 3). In the former
case, a second heteroatom, or an electron-donating sub-
stituent can augment the electron density of the ring, and
hence the binding and the ef®ciency of deuteration. The
results for substituted imidazoles, pyrazoles, and tetrazoles
are comparable to those for thiazoles but this does not,
unsurprisingly, extend to annelated derivatives: 2-amino-
benzothiazole, for example, was not deuterated at all.
Where the pyrrole-like nitrogen of a pyrazole or a tetrazole
was left unprotected, degradation of the substrate was a
dominant process. In the case of 3-34-chlorophenyl)pyra-
zole, some material could be recovered if a smaller quantity
of 1 was used, or the reaction time was reduced, but the
recovery remained poor. 3-Phenyl-5-aminopyrazole and
5-phenyltetrazole did not survive the reaction conditions
at all. Given that there does not appear to be any degradation
of phenylthiazoles or of 4-phenylimidazole under the reac-
tion conditions, and in view of the observed cleavage of
phenylhydrazine 3vide supra), it may be that where exten-
sive degradation occurs, this is a consequence of reductive
N±N cleavage. N-alkylated pyrazoles and tetrazoles can,
however, be good deuteration substrates 3Table 6, entries
13±16). It is not surprising that the 3-arylpyrazole 3entry 13)
undergoes more ef®cient deuteration than the 5-aryl isomer
3entry 14), since only the former has an sp2 nitrogen in a
position to direct deuteration. A similar comparison
between isomeric tetrazoles could not be made, since
1-benzoyl-5-phenyltetrazole decomposes under the reaction
conditions, while 1-benzyl-5-phenyltetrazole undergoes a
previously observed rearrangement,7 giving the 2-isomer
without apparent degradation.
The lone pairs of benzylic amines and alcohols are not co-
planar with the arene, but are nevertheless reasonably well
placed to direct deuteration. In practice, modest incorpora-
tion was observed with primary and secondary benzylic
amines 3Table 7), but there was no incorporation into a
tertiary amine. In the case of a-methylbenzylamine 3Table
7, entry 4), it was expected that the Thorpe±Ingold effect
Table 7. Deuteration of benzylic alcohol and amine derivatives mediated
by 1
Entry
X
R1
Equiv. 1
o-Da
1.0
1
2
3
4
5
6
NH2
H
H .7
H
Me.8
H .0
H
0.4
1.00
1
1.00
1.00
1.1
NHMe
NMe2
NH2
OH
NHAc
0.0
0.1
In addition to exchange in the aryl substituent, a number of
aryl heterocycles incorporate deuterium in the hetero-ring as
a
Figures presented are the average number of ortho-deuterium atoms
incorporated per molecule.
Scheme 3. Postulated process for incorporation of deuterium at C6 of pyridines.

G. J. Ellames et al. / Tetrahedron 57 .2001) 9487±9497
9493
Figure 2. Deuterium exchange into 4-phenylthiazole and ethyl 4-nitrobenzoate 3separate runs) over 48 h.
Figure 3. Deuterium exchange into 4-phenylthiazole and ethyl 4-nitrobenzoate 3single runs) over 22 h.
might facilitate metallacycle formation and thereby
exchange but, in practice, the incorporation was poorer
than into benzylamine itself. It is likely, once again, that
the differing results with differently-substituted amines are
simply the consequence of increasing steric encumbrance at
the nitrogen centre. In the cases of benzyl alcohol and
N-benzylacetamide, the poor results presumably re¯ect the
less nucleophilic character of the directing heteroatom.
mixtures of catalyst and substrate 3Fig. 2) and by sampling
of single exchange mixtures of each 3Fig. 3). In the former
case, the ®nal deuterium incorporations are comparable to
those quoted above. Nevertheless, the kinetics of the ortho-
deuterations are clearly different to those for the deuteration at
C-2 of 4-phenylthiazole, where the initial rate is very much
faster: this process is essentially complete in a matter of
minutes, whereas ortho-exchange in both substrates requires
around 8 h for completion. In fact, ethyl 4-nitrobenzoate
continued to incorporate small quantities of deuterium for
the whole of the period studied, indicating that such extended
periods are indeed necessary to ensure equilibration with
The rate of deuteration of two representative substrates,
4-phenylthiazole and ethyl 4-nitrobenzoate, was examined
by carrying out several simultaneous runs using the same
Table 8. Comparison between deuterations with 1 in dichloromethane and in methanol
Substrate
Deuterium incorp. 3DCM)a
Deuterium incorp. 3MeOH)a
4-Phe.n7y7lthiazol-2-amine
Benzamide
Benzyl alcohol
Ethyl benzoate
Phenylpyrazine
2.00
1.28
0.0
0.40
1.47
0.34
0.0
0.0
0.66
a
Figures presented are the average number of ortho-deuterium atoms incorporated per molecule.

9494
G. J. Ellames et al. / Tetrahedron 57 .2001) 9487±9497
Table 9. Key NMR and MS data for deuteration substrates
Substrate
Data
Acetanilide
Acetophenone
m/z 3EI) 135 3M1z), 93 3PhNH2
m/z 3EI) 1203M 1z), 105 3PhCO1)
)
1z
Acetophenone O-methyloxime
5-Acetyl-3-phenylisoxazole
Aniline
dH 3CDCl3) 2.25 33H, s), 4.01 33H,s), 7.4 33H, m), 7.68 32H, m, Hortho); m/z 3EI) 149 3M1z
m/z 3EI) 187 3M1z), 144 3[M2CH3CO]1)
)
m/z 3EI) 93 3M1z
)
Benzamide
m/z 3EI) 121 3M1z), 105 3PhCO1)
2-Benzamido-4-phenylthiazole
Benzenesulfonamide
Benzophenone
dH 3CD3SOCD3) 7.2±8.2 3m); m/z 3EI) 2803M 1z), 105 3PhCO1).
m/z 3EI) 157 3M1z), 77 3C6H5
)
1
m/z 3EI) 182 3M1z
H 3CDCl3) 1.8 34H, m), 2.7 32H, m, H2), 2.9 32H, m), 7.15±7.35 32H, m), 7.4 31H, m), 8.04 31H, d, Jˆ11 Hz, H9);
m/z 3EI) 1603M 1z
m/z 3EI) 135 3M1z), 108 3[M2HCN]1z
)
1-Benzosuberone
d
)
Benzothiazole
2-Benzoyl-5-phenyltetrazole
)
dH 3CD3SOCD3) 7.4±7.7 36H, m), 7.95 32H, d, Jˆ7.5 Hz, Hortho of 5-phenyl), 8.14 32H, d, Jˆ8.2 Hz, Hortho of
benzoyl); m/z 3EI) 222 3M1z), 105 3PhCO1)
N-Benzylacetamide
Benzyl alcohol
Benzylamine
N-Benzyldimethylamine
N-Benzylmethylamine
N-Benzyl-N-methylindole-2-
carboxamide
dH 3CDCl3) 1.94 33H, s), 4.35 32H, d, Jˆ6 Hz), 6.6 3br s), 7.4 35H, m); m/z 3EI) 149 3M1z), 106 3BnNH1)
1
m/z 3EI) 107 3M1z), 91 3C7H7
)
m/z 3EI) 106 3M1z
)
m/z 3EI) 135 3M1z), 134 3[M2H]1)
m/z 3EI) 121 3M1z), 1203[M 2H]1), 91 3C7H7
)
1
d
H 3CD3SOCD3) 3.23 3br s, 3H), 4.803br s, 2H), 6.8031H, br s), 7.03 3dd, 1H), 7.18 3dd, 1H), 7.25±7.5 3m, 7H),
7.57 3d, 1H). m/z 3EI) 264 3M1z), 120 3100%).
H 3CD3SOCD3) 6.00 32H, s), 7.4 35H, m, benzyl Ar-H), 7.55 33H, m), 8.05 32H, m, Hortho of 5-phenyl); m/z 3EI)
258 3M1z
H 3CDCl3) 0.96 33H, t), 1.4 32H, m), 1.6 32H, m), 3.5 32H, m), 6.15 31H, br s), 6.79 31H, s, H3), 7.12 31H, t), 7.28
31H, t), 7.42 31H, d), 7.63 31H, d), 9.42 31H, br s); m/z 3EI) 216 3M1z), 144 32-IndolylCO1)
H 3CD3SOCD3) 2.98 33H, s), 3.11 33H, s), 7.28 31H, m, H5), 7.34 31H, d, Jˆ7 Hz, H6), 7.55 31H, d, Jˆ8 Hz),
7.64 31H, s, H2); m/z 3EI) 226, 228 3[M2H]1), 183, 185 3ArCO1)
2-Benzyl-5-phenyltetrazole
d
)
N-Butylindole-2-carboxamide
d
3-Bromo-N,N-
d
dimethylbenzamide
3-Chloro-N,N-
dimethylbenzamide
d
H 3500 MHz, CD3SOCD3) 2.88 33H, br s), 2.97 33H, br s), 7.35 31H, ddd, Jˆ7.4, 1.5, 1.3 Hz, H4), 7.44 31H, dd,
Jˆ3.8, 1.5 Hz, H2), 7.45 31H, dd, Jˆ8.0, 7.4 Hz, H5), 7.50 31H, ddd, Jˆ8.0, 3.8, 1.3 Hz, H4); m/z 3EI) 183, 185
3M1z), 182, 184 3[M2H]1), 139, 141 3ArCO1)
3/5-34-Chlorophenyl)-1-
methylpyrazole
dH 3CDCl3) 3.803s), 6.303d, Jˆ2 Hz, H4 of 5-aryl), 6.503d, Jˆ2 Hz, H4 of 3-aryl), 7.3±7.4 3m), 7.43 3d,
Jˆ8.7 Hz, Hortho of 5-aryl), 7.52 3d, Jˆ2 Hz, H3 of 5-aryl), 7.72 3ddd, Jˆ8.6, 2.7, 1.7 Hz, Hortho of 3-aryl); m/z 3EI)
192 3M1z).
N-34-Chlorophenyl)-p-
toluenesulfonamide
N,N-Diisopropylbenzamide
d
H 3500 MHz, CD3SOCD3) 2.31 33H, s), 7.08 32H, ddd, Jˆ8.9. 2.7, 2.2 Hz), 7.28 32H, ddd, Jˆ8.9. 2.7, 2.2 Hz),
7.33 32H, dm, Jˆ8.3 Hz), 7.62 32H, dm, Jˆ8.3 Hz), 10.32 31H, br s).
dH 3500 MHz, CD3SOCD3) 1.25 312H, br), 3.62 32H, br), 7.25 32H, m), 7.39 33H, m); m/z 3EI) 205 3M1z), 105
3PhCO1)
N,N-Dimethylbenzamide
d
H 3500 MHz, 70oC, CD3SOCD3) 2.94 36H, s), 7.38 32H, m), 7.42 33H, m); m/z 3EI) 149 3M1z), 148 3[M2H]1),
105 3PhCO1)
N,N-Dimethyl-3-
¯uorobenzamide
N,N-Dimethyl-4-
¯uorobenzylamine
Dimethyl isophthalate
d
H 3CD3SOCD3) 2.88 33H, br s), 2.97 33H, br s), 7.2±7.25 32H, m), 7.27 31H, ddd, Jˆ9.1, 2.7, 0.9 Hz, H6), 7.47
31H, m); m/z 3EI) 167 3M1z), 166 3[M2H]1), 105 3PhCO1)
m/z 3EI) 153 3M1z), 152 3[M2H]1), 109 3C7H6F1)
dH 3CDCl3) 3.93 36H, s), 7.53 31H, m), 8.2032H, d, 11 Hz, H4, H6), 8.67 31H, s, H2); m/z 3EI) 194 3M1z), 163
3[M2MeO]1).
N,N-Dimethyl-3-
methoxybenzamide
d
H 3500 MHz, CD3SOCD3) 2.88 33H, br s), 2.96 33H, br s), 3.76 33H, s), 6.9031H, dd, Jˆ2.6, 1.5 Hz, H2), 6.92
31H, ddd, Jˆ7.6, 1.5, 1.1 Hz), 6.98 31H, ddd, Jˆ8.3, 2.6, 1.1 Hz, H6), 7.33 31H, dd, Jˆ8.3, 7.6 Hz); m/z 3EI) 179
3M1z), 178 3[M2H]1), 135 3ArCO1)
N,N-Dimethyl-4-
d
H 3CD3SOCD3) 3.02 36H, br s), 3.80 33H, s), 6.87 32H, d, Jˆ9 Hz), 7.37 32H, d, Jˆ9 Hz); m/z 3EI) 179 3M1z), 178
methoxybenzamide
4,4-Dimethyl-2-32-
methoxyphenyl)oxazoline
N,N-Dimethyl-4-
nitrobenzamide
Dimethyl phthalate
N,N-Dimethyl-3-
3[M2H]1), 135 3ArCO1)
dH 3CDCl3) 1.37 36H, s), 3.87 33H, s), 4.07 32H, s), 6.95 32H, m), 7.40 31H, t), 7.71 31H, dd, H6); m/z 3EI) 205
3M1z
d
)
H 3CD3SOCD3) 2.93 33H, s), 3.11 33H, s), 7.85 32H, d, Jˆ9 Hz), 8.24 32H, d, Jˆ9 Hz); m/z 3EI) 194 3M1z), 193
3M2H1), 1503ArCO 1
)
m/z 3EI) 194 3M1z), 163 3[M2MeO]1).
dH 3500 MHz, CD3SOCD3) 2.88 33H, br s), 2.99 33H, s), 7.67 31H, br dd, Jˆ7.9, 7.7 Hz), 7.71 31H, br d,
tri¯uoromethylbenzamide
N-Ethoxycarbonylbenzamidine
Jˆ7.9 Hz), 7.72 31H, br s), 7.8031H, br d, Jˆ7.7 Hz); m/z 3EI) 217 3M1z), 216 3[M2H]1), 173 3ArCO1)
d
H 3CDCl3) 1.34 33H, t, Jˆ6 Hz), 4.21 32H, q, Jˆ6 Hz), 7.4 32H, m), 7.5 31H, m), 7.85 32H, d, Jˆ7 Hz, Hortho); m/z
3CI) 193 3MH1), 165 3[MH-C2H4]1).
Ethyl benzoate
Ethyl 4-methoxybenzoate
m/z 3EI) 1503M 1z), 105 3PhCO1)
dH 3CD3SOCD3) 1.36 33H, t, Jˆ6 Hz), 3.84 33H, s), 4.33 32H, q, Jˆ6 Hz), 6.89 32H, d, Jˆ9 Hz), 7.98 32H, d,
Jˆ9 Hz); m/z 3EI) 1803M 1z), 135 3ArCO1)
Ethyl Nicotinate
d
H 3500 MHz, CD3SOCD3) 1.38 33H, t, Jˆ7.1 Hz), 4.39 32H, q, Jˆ7.1 Hz), 7.35 31H, ddd, Jˆ8.0, 4.8, 0.9 Hz),
8.26 31H, ddd, Jˆ8.0, 2.1, 1.9 Hz), 8.74 31H, dd, Jˆ4.8, 1.9 Hz), 9.2031H, dd, Jˆ2.1, 0.9 Hz); m/z 3EI) 151 3M1z),
106 3ArCO1)
Ethyl 4-nitrobenzoate
1-Indanone
d
H 3CD3SOCD3) 1.4033H, t, Jˆ7 Hz), 4.41 32H, q, Jˆ7 Hz), 8.18 32H, d, Jˆ8 Hz), 8.25 32H, d, Jˆ8 Hz); m/z 3EI)
195 3M1z), 1503ArCO 1
H 3CDCl3) 2.7 32H, m, H2), 3.15 32H, m), 7.2±7.5 32H, m), 7.4031H, m, H5), 7.74 31H, d, Jˆ7.5 Hz, H7); m/z
3EI) 132 3M1z
m/z 3EI) 1503M 1z), 135 3ArCO1)
H 3CDCl3) 3.45 33H, s), 3.84 33H, s), 7.11 31H, t), 7.28 31H, t), 7.47 31H, d), 7.71 31H, d), 9.65 31H, br s); m/z 3EI)
204 3M1z), 144 32-IndolylCO1)
)
d
)
4-Methoxyacetophenone
N-Methoxy-N-methylindole-2-
carboxamide
d

G. J. Ellames et al. / Tetrahedron 57 .2001) 9487±9497
9495
Table 9. 3continued)
Substrate
Data
2-34-Methoxyphenyl)thiophene
d
H 3CD3COCD3) 3.81 33H, s), 6.96 32H, d, Jˆ9 Hz), 7.08 31H, dd, Jˆ5.5, 6 Hz), 7.32 31H, d, Jˆ5.5 Hz), 7.36 31H,
d, Jˆ6 Hz), 7.59 32H, d, Jˆ9 Hz); m/z 3EI) 1903M 1z).
a-Methylbenzylamine
Methyl 2-Bromobenzoate
Methyl dithiobenzoate
m/z 3EI) 1203[M 2H]1), 106 3[M2CH3]1)
d
d
H 3500 MHz, CD3SOCD3) 3.85 33H, s), 7.48 32H, m), 7.74 32H, m); m/z 3EI) 214, 216 3M1z), 183, 185 3ArCO1)
H 3CD3SOCD3) 2.78 33H, s), 7.48 32H, t, Jˆ8 Hz), 7.64 31H, t, Jˆ8 Hz), 7.96 32H, d, Jˆ8 Hz, Hortho); m/z 3EI)
168 3M1z), 121 3PhCS1).
N-Methyl-N-phenylindole-2-
carboxamide
dH 3CD3SOCD3) 3.38 3s, 3H), 6.9031H, t), 7.11 31H, t), 7.27 31H, d), 7.35 33H, m, H4, H o), 7.45 34H, m, H3, Hm,
Hp); m/z 3EI) 251 3M1z), 145, 107.
m/z 3EI) 1403M 1z), 125 3[M2CH3]1)
m/z 3EI) 156 3M1z), 141 3[M2CH3]1)
Methyl phenyl sulfoxide
Methyl phenyl sulfone
4-Nitroacetophenone
4-Nitroacetophenone
dimethylhydrazone
4-Nitroacetophenone
phenylhydrazone
Nitrobenzene
Phenol
Phenyl acetate
Phenylhydrazine
4-Phenylimidazole
m/z 3EI) 165 3M1z), 1503ArCO 1
)
m/z 3EI) 207 3M1z
)
m/z 3EI) 255 3M1z), 117 3PhC3Me)vNH1)
m/z 3EI) 123 3M1z), 77 3C6H51).
m/z 3EI) 94 3M1z
)
m/z 3EI) 136 3M1z), 94 3PhOH1z).
m/z 3EI) 108 3M1z), 92 3PhNH1).
dH 3CD3SOCD3) 7.15 31H, m), 7.35 32H, m), 7.62 31H, s, H5), 7.72 31H, s, H2), 7.78 32H, m, Hortho); m/z 3EI) 144
3M1z), 116 3[M2HCN]1z
)
N-Phenylmethanesulfonamide
N-Phenylmethanesulfonimide
Phenylpyrazine
m/z 3EI) 171 3M1z), 92 3PhNH1)
m/z 3EI) 249 3M1z), 171 3PhNHMs1z), 92 3PhNH1).
d
H 3CDCl3) 7.5 33H, m), 8.00 32H, d, Jˆ8 Hz, Hortho), 8.49 31H, br s), 8.64 31H, br s), 9.03 31H, s); m/z 3EI) 156
3M1z
H 3500 MHz, CD3SOCD3) 6.53 31H, dd, Jˆ2.3, 2.0Hz), 7.29 31H, dt, Jˆ7.6, 1.1 Hz), 7.48 31H, dddd, Jˆ8.6, 7.6,
2.2, 1.9 Hz), 7.73 31H, dd, Jˆ2.0, 0.6 Hz), 7.83 31H, ddd, Jˆ8.6, 0.9, 0.7 Hz), 8.47 31H, dd, Jˆ2.3, 0.6 Hz); m/z
3EI) 144 3M1z), 116 3[M2HCN]1z
H 3500 MHz, CD3SOCD3) 7.34 31H, ddd, Jˆ7.4, 4.9, 1.2 Hz), 7.42 31H, m), 7.48 31H, ddm, Jˆ8.0, 7.6 Hz), 7.86
31H, ddd, Jˆ8.0, 7.4, 1.8 Hz),7.94 31H, ddd, Jˆ8.0, 1.2, 1.1 Hz), 8.07 31H, dm, Jˆ8.0, Hz), 8.66 31H, ddd, Jˆ4.9,
1.8, 0.9 Hz, H6); m/z 3EI) 155 3M1z), 127 3[M2HCN]1z
H 3CDCl3) 7.2031H, t, Jˆ6 Hz), 7.5 33H, m), 8.46 32H, dd, Jˆ7, 3 Hz, Hortho), 7.82 32H, d, Jˆ6 Hz); m/z 3EI) 156
3M1z), 103 3PhCvN1z
H 3CD3SOCD3) 7.25±7.6 33H, m), 7.65 31H, m, Ho), 8.1031H, d, H5), 8.2031H, m, H o), 8.86 31H, d, H6), 9.24
)
1-Phenylpyrazole
2-Phenylpyridine
d
)
d
)
2-Phenylpyrimidine
4-Phenylpyrimidine
d
)
d
31H, s, H2); m/z 3EI) 156 3M1z), 129 3[M2HCN]1z
)
4-Phenylthiazol-2-amine
2-Phenylthiazole
d
d
H 3CD3SOCD3) 7.05 33H, m, H5, NH2), 8.00 32H, d, Jˆ8 Hz, Hortho); m/z 3EI) 176 3M1z), 134 3[M2H2NCN]1z
)
H 3CD2Cl2) 7.37 31H, d, Jˆ3.5 Hz), 7.4±7.5 33H, m), 7.85 31H, d, Jˆ3.5 Hz), 8.032H, m, H ortho); m/z 3EI) 161
H 3CD2Cl2) 7.4 33H, m), 7.58 32H, d, Jˆ8 Hz, Hortho), 8.08 31H, s), 8.75 31H, s); m/z 3EI) 161 3M1z), 134
3M1z), 134 3[M2HCN]1z
)
5-Phenylthiazole
1-Tetralone
d
3[M2HCN]1z
)
d
H 3CDCl3) 2.15 32H, m), 2.65 32H, m, H2), 2.97 32H, t, Jˆ6.5 Hz), 7.25 32H, m), 7.46 31H, m), 8.02 31H, d,
Jˆ7 Hz, H8); m/z 3EI) 146 3M1z), 903C 7H61).
poorer substrates. Interestingly, when the exchange system
was perturbed by the removal of sample 3despite the
continuous maintenance of a positive pressure of deuterium)
the ®nal level of ortho-deuteration was essentially halved.
This may be a consequence of air ingress during sampling,
but it appears that for both substrates, the initial rate of ortho-
exchange is comparable to that in the undisturbed systems, but
slows within little more than an hour. Exchange of thiazole-
H2, interestingly, is slower than in the undisturbed system, but
eventually does occur to essentially the same extent, again
suggesting the operation of a different mechanism such as
the reversible hydrogenation postulated above. That the
observed saturation behaviour and the reduced levels of
incorporation are not solely consequences of irreversible
inactivation of the metal catalyst was demonstrated by addi-
tion, after 22 h, of fresh 4-phenylthiazole to the mixture
containing ethyl 4-nitrobenzoate and replenishing the deuter-
ium atmosphere. After a further 90min, this had incorporated
1.0D in ortho positions, indicating that iridium species were
still active. Although it is clear that shorter exposure times
would suf®ce in many cases, deuterations carried out in the
course of this work were generally allowed at least 22±24 h to
reach equilibrium.
Published results indicate that iridium-mediated deutera-
tion, in general, is intolerant of more polar, and particularly
hydroxylic, solvents.1±3 We have found, however, that the
better substrates still undergo some deuteration even in neat
methanol 3Table 8) and good results can be obtained by
using dichloromethane containing small quantities of
methanol as a co-solvent. Given that sulfoxides do not
appear to be good substrates 3Table 4, entry 12), dimethyl-
sulfoxide was also investigated as a co-solvent, but it was
found that as little as 10% 3based on the solvent volume) of
DMSO completely suppressed the exchange of aceto-
phenone with deuterium in the presence of 1.
2. Conclusions
From the results presented here, it emerges that
exchange of protons mediated by 1 is directed most
ef®ciently by a functional group containing an sp2-
hybridised nitrogen or oxygen atom, via
a ®ve-
membered metallacycle. In general, increasing the elec-
tron density at the directing heteroatom increases the
degree of deuterium incorporation, although certain

9496
G. J. Ellames et al. / Tetrahedron 57 .2001) 9487±9497
substrates such as N-unsubstituted amidines and dithio-
carboxylates do not survive the exchange conditions.
The electronic effects of substituents in the arene ring
are critical only where the directing group is poor, in
which case exchange is generally promoted by electron
donating substituents, but meta-substituents or bulky
substituents attached to the directing heteroatom impede
the exchange process. Where one ortho-substituent was
present, there was no sign of any effect upon exchange
at the other ortho-position, and there was no sign that
an ortho-halogen, for instance, might be exchanged.
Collateral exchange of protons adjacent to nitrogen is
observed and may occur by a related C±H activation
process, while deuterium incorporation into heterocycles
is observed in a few cases, possibly by means of a
reversible partial hydrogenation.
potassium acetate and 18-crown-6,30 gave 2-34-methoxy-
phenyl)furan 335%), mp 50±548C 3lit.31 55±588C). dH
3CD3COCD3) 3.82 33H, s), 6.48 31H, dd, Jˆ4.5, 2.5 Hz,
d), 6.67 31H, d, Jˆ4.5 Hz), 6.96 32H, d, Jˆ9.6 Hz), 7.54
31H, d, Jˆ2.5 Hz), 7.63 32H, d, Jˆ9.6 Hz); m/z 174 3M1,
100%), 159 3M2CH3), 131 3159-CO). Similarly prepared
was 2-34-methoxyphenyl)thiophene 324%), mp 104±1068C
3lit.31 104±1078C). dH 3CD3COCD3) 3.82 33H, s), 6.96 32H,
d, Jˆ10Hz), 7.08 31H, dd, Jˆ4, 4 Hz), 7.31 31H, d,
Jˆ4 Hz), 7.36 31H, d, Jˆ4 Hz), 7.59 32H, d, Jˆ10Hz);
m/z 1903M 1, 100%), 175 3M2CH3), 147 3175-CO).
3.1.2. tert-Butyl 2-isopropylphenylcarbamate. A solution
of 2-isopropylaniline 35.481 g, 40mmol) and di- tert-butyl
dicarbonate 310.915 g, 50 mmol) in 1,2-dichloroethane
350ml) was stirred for 4 h at 50±60 8C, then left to cool
overnight. The mixture was concentrated under reduced
pressure to a low volume and passed through a short column
of silica gel, eluting with ethyl acetate±hexane 31:9) to give
tert-butyl 2-isopropylphenylcarbamate 311.503 g, 100%) as
a reddish oil. nmax 3344, 2967, 2932, 2870, 1731, 1714,
1703, 1587, 1514 cm21; dH 3CDCl3) 1.11 36H, d,
Jˆ7.5 Hz), 1.5039H, s), 3.01 31H, septet, Jˆ7.5 Hz), 6.24
31H, br s), 7.05±7.25 3m, 3H, 7.64 31H, d, Jˆ8.4 Hz); m/z
3NH3±CI) 253 3MNH41), 236 3MH1), 197, 180, 135
3MH1±HCOO±t-Bu, 100%), 120; HRMS found:
253.1911 3calcd for C14H25N2O2 253.1916).
3. Experimental
3.1. General
Gas chromatography was performed using a Hewlett±
Packard chromatograph 3HP 5890) ®tted with a mass-
selective detector 3HP 5970MSD) on a capillary column
3HP1, 30m £0.25 mm; 0.25 mm layer); the injector
temperature was 2508C and the oven temperature was
increased, after an initial 2 min delay, either from an initial
70±2008C at 58C min21, or from an initial 100 to 2408C at
108C min21. Additional low-resolution mass spectra and
high resolution mass spectra were recorded using a VG
Autospec magnetic sector instrument. 1H NMR spectra
were recorded using Jeol GSX-270and Bruker 500
instruments. 3Cyclooctadiene)3pyridine)3tricyclohexylphos-
phine)iridium3I) hexa¯uorophosphate 31) was obtained
from Fluka and from Strem
3.1.3. 4-Phenyl-2-butanone )4) and phenylacetone )3).
Magnesium 30.50 g) was dry-stirred for 30 min in a nitrogen
atmosphere, then suspended in THF 37.5 ml). 1,2-Di-
bromoethane 30.020 ml) was added, the mixture was heated
to re¯ux for 30min, and 2-bromoethylbenzene 31.0ml,
7.3 mmol) was added. After a further 15 min at re¯ux, the
mixture was cooled and the supernatant solution was added
to a solution of N-methoxy-N-methylacetamide32 in THF
35 ml) at 2208C. After 90min, the mixture was quenched
with hydrochloric acid 31 M) and extracted twice with tert-
butyl methyl ether. The combined organic phases were
washed with aqueous sodium hydrogencarbonate, dried
3MgSO4), and evaporated under reduced pressure to leave
4-phenyl-2-butanone 30.783 g, 72%) as a pale yellow oil.
Which was distilled at 1308C/20mmHg 3lit. 33 bp 116±
1188C/20mmHg). dH 3CDCl3) 2.12 33H, s), 2.74 32H, t,
Jˆ7.9 Hz), 2.88 32H, t, Jˆ7.9 Hz), 7.13±7.19 33H, m),
7.2±7.3 32H, m). m/z 148 3M1), 133 3M2CH3), 105
3100%), 91. Similarly prepared was phenylacetone 340%),
bp 1108C/20mmHg 3lit. 34 bp 107±1098C/24 mmHg). dH
3CDCl3) 2.15 33H, s), 3.69 32H, s), 7.15±7.4035H, m).
m/z 134 3M1), 91 3100%).
Acetophenone O-methyloxime,11 2-benzamido-4-phenyl-
thiazole,12 2-benzoyl-5-phenyltetrazole,13 2-benzyl-5-
phenyltetrazole,14
3-34-chlorophenyl)-1-methylpyrazole
and 5-34-chlorophenyl)-1-methylpyrazole,15 dimethyl-4-
¯uorobenzylamine,16 4,4-dimethyl-2-32-methoxyphenyl)-
oxazoline,17 N-ethoxycarbonylbenzamidine,18 N-methoxy-
N-methylindole-2-carboxamide,19 other indole-2-carbox-
amides,20 methyl dithiobenzoate,21 4-nitroacetophenone
dimethylhydrazone,22 4-nitroacetophenone phenylhydra-
zone,23 N-phenylmethanesulfonamide and N-phenylmethane-
sulfonimide,24 phenylpyrazine and 2-phenylpyrimidine,25 2-
and 5-phenylthiazole,26 and 4-phenylthiazole,27 were
prepared using published procedures. N-Benzylacetamide
was obtained as a side-product from the benzylamine-
mediated deprotection of glucose penta-O-acetate.28 Ethyl
esters and substituted benzamides, all of which were known
compounds, were prepared by treatment of the correspond-
ing acid chloride with ethanol or with an appropriate
amine.29 Key NMR signals and mass spectrometric ions
used in the determination of deuterium incorporation levels
are summarised in Table 9. Other substrates were obtained
commercially, or were prepared as described below.
3.1.4. Example procedure for deuterium exchange. A
25 ml ¯ask containing 4-phenylthiazole 314 mg, 87 mmol)
and 1 380mg, 100mmol) in dichloromethane 31 ml)
containing deuterium oxide 3one drop) was evacuated,
¯ushed with deuterium, and stirred for 90h at room
temperature. The crude mixture was puri®ed directly by
preparative TLC on silica gel in hexane±ethyl acetate
395:5) to give [thiazole-2-2H, benzene-2,6-2H2]-4-
phenylthiazole 311 mg). dH 3CDCl3) 7.36 31H, t, Jˆ
7.5 Hz), 7.44 32H, d, Jˆ7.5 Hz), 8.00 30.2H, d, Jˆ7.5 Hz,
benzene-H-2/6), 8.16 31H, s, thiazole-H-5), no peak at 9.20
3thiazole-H-2). m/z 164 3M1, 100%), 136 3M22HCN).
3.1.1. 2-)4-Methoxyphenyl)furan and 2-)4-methoxy-
phenyl)thiophene. Coupling of 4-methoxybenzene-
diazonium tetra¯uoroborate with furan, in the presence of

G. J. Ellames et al. / Tetrahedron 57 .2001) 9487±9497
9497
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11. Beak, P.; Basha, A.; Kokko, B.; Loo, D. J. Am. Chem. Soc.
1986, 108, 6016.
Acknowledgements
The authors wish to thank Dr S. J. Byard for NMR spectra
and Dr T. Drans®eld 3University of York) for high
resolution mass spectra.
12. Fromm, E.; Kapeller-Adler, R.; Friedenthal, W.; Stangel, L.;
Edlitz, J.; Braumann, E.; Nussbaum, J. Liebigs Ann. 1928,
467, 240.
13. Kreutzer, P. H.; Weis, J. Ch.; Bock, H.; Erbe, J.; Beck, W.
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