The effect of adding Crabtree's catalyst to rhodium black in direct hydrogen isotope exchange reactions

Article abstract of DOI:10.1002/jlcr.1612

A new catalytic system based on rhodium black using Crabtree's catalyst as an additive for direct hydrogen isotope exchange in aromatic compounds has been investigated. The level of deuterium incorporation can be improved from for example 16 to 93%. The new catalyst mixture tolerates a variety of solvents. Copyright

Full text of DOI:10.1002/jlcr.1612

Research Article
Received 9 February 2009,
Revised 4 May 2009,
Accepted 6 May 2009
Published online 23 June 2009 in Wiley Interscience
(www.interscience.wiley.com) DOI: 10.1002/jlcr.1612
The effect of adding Crabtree’s catalyst to
rhodium black in direct hydrogen isotope
exchange reactions
Ã
Søren Christian Schou
A new catalytic system based on rhodium black using Crabtree’s catalyst as an additive for direct hydrogen isotope
exchange in aromatic compounds has been investigated. The level of deuterium incorporation can be improved from for
example 16 to 93%. The new catalyst mixture tolerates a variety of solvents.
Keywords: rhodium black; Crabtree’s catalyst; deuterium; catalytic direct hydrogen isotope exchange
Introduction
+
PCy3
Isotopically labelled compounds are important in the screening
of pharmaceutical candidates in drug development pro-
Ir
PF6-
N
grammes. Such compounds facilitate studies of pharmacoki-
netics and metabolism, as well as other important assays. Owing
to an increased attention to speed for drug development and
Figure 1. Crabtree’s catalyst.
the quality of the drug candidate, isotopically labelled
compounds have to be prepared, preferably in a fast and
efficient way. The synthesis of labelled compounds can often be
laborious and synthetically challenging. The use of catalysts for
#
O
direct exchange of hydrogen isotopes can ameliorate some of
these difficulties associated with the preparation of isotopically
labelled compounds because no synthesis of appropriate
precursor is required.
O
N
O
H
H
N
N
Recently, Alexakis et al.1 reported the use of heterogeneous
systems in THF as suitable catalysts for promoting hydrogen
isotope exchange in pyridines and other nitrogen heteroaro-
matic compounds. These catalytic systems were based on group
VIII metals such as rhodium or ruthenium, used as rhodium
black, rhodium on alumina or ruthenium black.
O
N
¤
Figure 2. The structure of 1. Marks indicate sites for anticipated deuteration using
Crabtree’s catalyst (]) and Rhodium black (¤).
Crabtree’s catalyst, [Ir(COD)(PCy3)(Py)]PF6, is a homogeneous
catalyst based on iridium, coordinated to pyridine and
tricyclohexyl phosphine (Figure 1). Crabtree’s catalyst is a well-
established catalyst used for hydrogen isotope exchange
reactions.2–9 It is able to promote deuterium or tritium
incorporation into arenes at positions ortho to a directing group
such as the carbonyl group.2–4, 6–9
anticipated to effect H/D-exchange in the ortho-position to the
pyridine nitrogen (Figure 2) and finally a third experiment where
a mixture of the two catalysts was used to potentially provide
the dilabelled form of 1. To our surprise there was little or no
incorporation of deuterium using either Crabtree’s catalyst
(no incorporation) or rhodium black (16% incorporation ortho to
pyridine nitrogen). However, using the mixture an incorporation
Here we report improvements that can be obtained by
adding Crabtree’s catalyst to rhodium black.
Results and discussion
As part of a medicinal chemistry programme we were interested
in labelling compound 110 with deuterium. Three experiments
were set up, one using Crabtree’s catalyst that was expected to
promote H/D-exchange in the ortho-position to the carbonyl
group, a second experiment using rhodium black that was
LEO Pharma, Medicinal Chemistry Research, Industriparken 55, DK-2750
Ballerup, Denmark
*Correspondence to: Søren Christian Schou, LEO Pharma, Medicinal Chemistry
Research, 55 Industriparken, DK-2750 Ballerup, Denmark.
E-mail: soeren.schou@leo-pharma.com
J. Label Compd. Radiopharm 2009, 52 376–381
Copyright r 2009 John Wiley & Sons, Ltd.

S. C. Schou
level of 93% deuterium was observed in the position ortho to
the nitrogen in the pyridine ring.
We conclude that the mechanism of the mixture relates to
rhodium black, because the enhanced level of incorporation in
To further investigate this surprising observation a set of all cases are seen in the ortho-position to the pyridine nitrogen,
experiments were undertaken to test the generality of the the same position involved when rhodium black is used alone.
catalyst mixture in comparison with the single catalysts. We The catalytic effect of rhodium black can be enhanced by
investigated substrates that were electron rich, electron poor adding Crabtree’s catalyst, while there is no enhanced catalytic
and sterically hindered pyridines (Table 1).
effect of Crabtree’s catalyst when rhodium black is added. In two
As shown in Table 1 (entries 2, 3, 4, 6, 7, 8 and 15), there is a cases, only the mixture was able to promote hydrogen isotope
clear trend towards greater incorporation of deuterium, exchange (entries 11 and 14), indicating that a new and more
although not all compounds show increased incorporation of active catalytic system is at hand.
deuterium using the catalyst mixture.
A hypothesis for the enhanced effect may involve a ligand
In the 2-substituted pyridines the most significant enhancement transfer from Crabtree’s catalyst to rhodium. To investigate
was observed using the mixture, except entry 1, where a lower this hypothesis, a set of experiments using 1 as model compound
incorporation in the 6-position is observed. In 2-phenyl-pyridine were undertaken, where one or more of the components of
(entry 10) incorporation of deuterium in the 2- and 6- position of Crabtree’s catalyst were added to rhodium black (Scheme 1 and
the phenyl group was also observed. The same deuteration pattern Table 2).
has earlier been reported using rhodium(III) hydride complexes but
It was possible to improve the catalytic effect of rhodium
with lower level of deuterium incorporation (9%) in the pyridine black (Table 2) (from 16% to 42% deuterium incorporation), but
ring.11 Ellames et al.12 has investigated the use of iridium based not to the same extent as adding Crabtree’s catalyst (93%
catalysts of the general form [Ir(PR3)2(COD)]1 for their capability of incorporation). The most effective additive was pyridine (entry 15);
promoting H/D isotope exchange. Using PCy3 as ligand, which is however, the addition of larger amounts of pyridine did not
the closest catalyst related to Crabtree’s catalyst, they found no promote further deuterium incorporation (entries 16 and 17). To
incorporation of deuterium into the phenyl group but a level of investigate whether the enhanced effect of pyridine was an additive
deuterium incorporation of 50% in the C6-position of the pyridine effect to rhodium black, pyridine was tested in absence of catalyst,
ring. Surprisingly we found no incorporation of deuterium into the and, as expected, no incorporation could be detected (entries 18
pyridine ring using the iridium based Crabtree’s Catalyst. No and 19). This indicates that the enhanced catalytic exchange
incorporation was observed in the substituent of 2-isopropyl- reaction takes place at the rhodium surface.
pyridine (entry 11), but in this compound attempted exchange
To test this hypothesis, an experiment was undertaken where
with rhodium black alone gave a reaction mixture with no trace of Crabtree’s catalyst and rhodium black were stirred under
starting material. The catalyst mixture, however, gave 80% D2-atmosphere for 4 h without 1 added. The heterogeneous
deuterium incorporation. Whether deuterium was incorporated catalytic mixture was then centrifuged and divided into solid
before or after degradation of 2-isopropyl-pyridine using rhodium and solution and each part was then added 1 and stirred under
black was not determined.
D2-atmosphere for 4 h. The solid was able to promote an
Using electron rich pyridines (entries 12 and 13) the effect of incorporation of 24% deuterium, while no incorporation of
adding Crabtree’s catalyst to rhodium black was less noticeable deuterium was observed in the solution, supporting that the
due to the high level of deuterium incorporation using rhodium catalytic exchange takes place exclusively on the rhodium
black alone.
Concerning the electron poor pyridines, no enhanced effect was
surface and not in solution.
Table 3 shows the effect of adding increasing amounts of
observed by adding Crabtree’s catalyst to rhodium black. In some Crabtree’s catalyst to rhodium black. Even a low amount
cases (entries 2 and 3) high levels of deuterium incorporation were (0.05 eq.) of Crabtree’s catalyst was able to enhance the catalytic
resulting from using rhodium black alone; in other cases (entries 1 effect of rhodium black noticeable, enhancing the incorporation
and 9) no significant enhancement was observed.
To investigate the scope, two aromatic non-pyridyl com-
level from 16 to 32% (entry 3).
Table 4 shows the effect of varying reaction times, and a high
pounds, one benzene nucleus and one pyrimidine scaffold were level of deuterium incorporation can be seen after only 1.5 h,
tested. In agreement with the results reported by Ellames et al.2 and after 3 h an incorporation level of 90% was observed,
we found that aniline (entry 15) did not undergo exchange indicating a highly active catalytic system.
using Crabtree’s catalyst. Using rhodium black we found it
Table 5 shows the catalytic effect of different rhodium
possible to obtain a level of deuterium incorporation of 51% and sources. All the tested sources of rhodium were able to promote
using the mixture a level of deuterium incorporation of 72% was catalytic hydrogen isotope exchange except non-amorphous
obtained. Using Crabtree’s catalyst or rhodium black, no rhodium, which was unable to promote exchange.
incorporation of deuterium in 4-amino-pyrimidine-5-carboxylic
acid (entry 14) was obtained. On the other hand using the was observed, noticeable when Crabtree’s catalyst was added.
mixture an incorporation of 60% deuterium was observed. Rhodium on different supports was quite active even without
A batch variation of the different rhodium black sources
Sometimes, just an additive effect was observed using the activation with Crabtree’s catalyst. An explanation for the
catalyst mixture, but less than an additive effect was also high catalytic activity could be that rhodium on support has a
observed (entry 1). The effect of the catalyst mixture cannot be larger surface area than non-amorphous rhodium or even rhodium
predicted and must be determined by experiments. Most black.
important, however, is the surprisingly positive outcome that
To test the robustness of the catalytic mixture, experiments in
sometimes can be found using the catalyst mixture, and different solvents were performed (Table 6). The catalytic system
substrates not able to undergo direct hydrogen isotope is more or less independent of the solvent, and acceptable to
exchange using Crabtree’s catalyst or rhodium black alone can high incorporation levels were observed in all solvents except
be labelled using the catalyst mixture (entry 14).
diethyl ether, which could be due to low solubility of 1.
J. Label Compd. Radiopharm 2009, 52 376–381
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

S. C. Schou
Table 1. Deuteration of substituted pyridines, pyrimidine and benzene using Crabtree’s catalyst, rhodium black or the mixture
Mixturec
Crabtree’s catalysta
Rhodium blackb
Entry
Substrate
2
3
4
5
6
2
3
4
5
6
2
3
4
5
6
% incorporation of deuterium in the given position
1
2
—
0
0
0
0
0
0
0
0
—
23
28
—
9
0
0
0
55
96
—
41
25
—
16
0
0
0
28
96
—
3
4
5
0
—
0
0
0
—
0
0
0
0
0
24
0
98
—
93
12
0
—
0
12
0
98
67
95
98
—
94
24
0
—
0
24
0
98
87
93
—
0
—
0
0
—
0
0
6
7
—
—
23
0
—
—
0
0
31
13
—
—
0
0
—
—
0
0
73
69
—
—
11
0
—
—
0
0
95
95
8
—
0
25
0
—
—
0
18
0
87
0
—
28
—
—
0
0
0
—
—
0
0
0
0
64
28
71
—
29
—
—
25
0
—
—
0
25
0
96
29
67
80
9
10d
11
—
—
0
0
0
0
0
e
#
e
#
e
#
e
0
0
0
0
#
0
0
0
12
13
14
—
0
0
0
0
0
0
0
0
0
—
97
0
0
44
0
0
0
81
97
0
—
97
0
21
0
0
0
85
97
0
—
—
—
—
—
—
0
—
—
—
—
60f
—
—
15
0
0
0
0
0
25
0
0
0
25
36
0
0
0
36
aExperimental conditions: Substrate (0.016 mmol), Crabtree’s catalyst (0.008 mmol), dry DCM (3 mL), D2 (1342–1590 mbar), RT, 4 h.
bExperimental conditions: Substrate (0.016 mmol), Rh black (0.010 mmol), dry THF (3 mL), D2 (1342–1590 mbar), RT, 4 h.
cExperimental conditions: Substrate (0.016 mmol), Crabtree’s catalyst (0.008 mmol), Rh black (0.010 mmol), dry DCM:THF
(1:1)(3 mL), D2 (1342–1590 mbar), RT, 4 h.
dIncorporation of D in the Ph-ring in the 2- and 6-position (Crabtree’s catalyst: 88%; Rhodium black: 32%; Mixture: 75%)
eNo trace of starting material. Experiment repeated twice with the same outcome.
fExperiment repeated three times.
Consequently, the high solvent tolerance expands the scope was purchased from Isotec. Anhydrous solvents were dried over
˚
and usefulness for the catalyst mixture, allowing a variety of molecular sieves (4 A). All other solvents and reagents were used
compounds to be labelled.
as received, purchased from Sigma-Aldrich, ABCR, Fluka, Alfa
1
Aesar and Acros. H and 13C NMR spectra were obtained on a
Experimental
Bruker AV600 spectrometer with a 5 mm TCI-Cryoprobe or a
Bruker DRX500 spectrometer with a 5 mm PAPPI-probe. The
deuterium content was measured on the basis of integration.
Chemical shifts are reported in ppm with tetramethylsilane
(TMS, d = 0.00) as internal reference.
General
All reactions were performed in a stainless steel manifold
purchased from RC Tritec, Teufen, Switzerland. D2 (99.8 at% D)
www.jlcr.org
Copyright r 2009 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2009, 52 376–381

S. C. Schou
O
N
Table 3. Incorporation of deuterium using different
amounts of Crabtree’s catalyst
O
O
D2
Rh black
Additive
O
Entry
Rhodium black
Crabtree’s catalyst
%D
O
D
N
O
H
H
H
H
N
N
N
N
THF:DCM (1:1)
RT, 4h
1
2
3
4
5
0.6
0.6
0.6
0.6
0.6
0
16
16
32
46
93
N
O
N
O
0.02
0.05
0.1
0.5
1
Scheme 1. Setup to investigate a possible ligand transfer.
Experimental conditions:
1
(0.016 mmol), Rh black
Table 2. Deuteration of 1 using different catalyst compo-
nents
(0.010 mmol), Crabtree’s catalyst, dry THF:DCM (1:1)(3 mL),
D2 (1463–1575 mbar), RT, 4 h. Numbers in table are numbers
of equivalents added.
Entry
Ir
Ir(COD)Cl Rh(COD)Cl PCy3
0.5
Py
%D
1
2
3
4
0.5
0.5
0.5
0.5
16
35
26
27
0
0.5
0.5
0.5
Table 4. Incorporation of deuterium observed as a func-
tion of time
5
0.5
6
7
8
9
0.5
0.5
0.5
0.5
0.5
20
16a
13
11
17
34
26
27b
23b
42
35b
25c
0
Entry
Crabtree’s catalyst
Reaction time
%D
0.5
0.5
1
2
3
4
0
2 h
1.5 h
2 h
4
69
84
90
0.6
0.6
0.6
0.6
0.5
0.5
0.5
10
11
12
13
14
15
16
17
18d
19d
0.5
0.5
0.5
0.5
3 h
0.5
0.5
0.5
Conditions: 1 (0.016 mmol), Rh black (0.010 mmol), Crabtree’s
catalyst, dry THF:DCM (1:1)(3 mL), D2 (1340–1410 mbar) for
the given time at RT. Numbers in table are numbers of
equivalents added.
0.5
1
10
0.5
1
0
Entry 1
1H NMR (500 MHz, CDCl3)d 8.79–8.74 (m, 1H, C6-H), 8.14
(d, J = 7.8 Hz, 1H, C3-H), 7.85 (td, J = 1.7 and 7.7 Hz, 1H, C4-H),
7.48 (ddd, J = 1.0, 4.7 and 7.6 Hz, 1H, C5-H), 4.49 (q, J = 7.2 Hz, 2H,
OCH2CH3), 1.45 (t, J = 7.1 Hz, 3H, OCH2CH3).
Entry 2
1H NMR (500 MHz, DMSO-d6)d 9.14–9.07 (dd, J = 0.6 and
2.0 Hz, 1H, C2-H), 8.83 (dd, J = 1.7 and 4.8 Hz, 1H, C6-H), 8.30 (dt,
J = 2.0 and 8.0 Hz, 1HC4-H), 7.58 (ddd, J = 0.6, 4.8 and 8.0 Hz, 1H,
C3-H), 4.37 (q, J = 7.1 Hz, 2H, OCH2CH3), 1.35 (t, J = 7.1 Hz, 3H,
OCH2CH3).
aNo deuteration is also observed if 0.5 eq. NH4PF6 is added.
bSame incorporation level observed if 0.5 eq. COD is added.
cUnknown impurity formed.
dNo rhodium black added. Experimental conditions:
1
(0.016 mmol), Rh black (0.010 mmol), catalyst component/
components, dry THF:DCM (1:1)(3mL), D2 (1457–1639 mbar),
RT, 4 h. Numbers in table are numbers of equivalents added.
General procedure for deuterium exchange reaction
Entry 3
1H NMR (600 MHz, DMSO-d6)d 8.89–8.78 (m, 2H, C2,6-H),
7.90–7.80 (m, 2H, C3,5-H), 4.45–4.34 (m, 2H, OCH2CH3), 1.37 (dd,
J = 5.1 and 12.7 Hz, 3H, OCH2CH3).
Catalyst was weighed into an 8 mL round bottom reaction flask
containing a new teflon coated stir bar (3 Â 10 mm), substrate
(0.016 mmol) was dissolved in dry solvent (3 mL) and added. The
reaction mixture was frozen in liquid N2 and evacuated (below
3.5 Â 10À3 mbar), thawed and then stirred under D2-atmosphere
(1340–1666 mbar) for 4 h at RT. The reaction mixture was filtered
through a syringe-filter (Whatman, 0.45 mm) and concentrated in
vacuo.
Entry 4
1H NMR (500 MHz, DMSO-d6)d 8.49–8.41 (m, 1H, C6-H), 7.89
(td, J = 2.0 and 7.7 Hz, 1H, C4-H), 7.53 (dd, J = 0.7 and 8.1 Hz, 1H,
C3-H), 7.44 (ddd, J = 0.9, 4.9 and 7.2 Hz, 1H, C5-H).
Entry 5
1H NMR (500 MHz, DMSO-d6)d 8.64 (d, J = 2.6 Hz, 1H, C2-H),
8.56 (dd, J = 1.2 and 4.7 Hz, 1H, C6-H), 7.94 (ddd, J = 1.5, 2.5 and
8.2 Hz, 1H, C4-H), 7.47 (dd, J = 4.8 and 8.3 Hz, 1H, C5-H).
Entry 6
NMR-data for non-deuterated compounds
Entry numbers refer to Table 1.
Compound 1
1H NMR (500 MHz, DMSO-d6)d 8.43 (d, J = 5.5 Hz, 1H, C1-H),
1H NMR (500 MHz, DMSO-d6)d 8.12 (d, J = 5.3 Hz, 1H, Py-C6-H), 7.86–7.74 (m, 1H, C5-H), 7.67–7.56 (m, 1H, C4-H).
8.07 (dd, J = 1.5 and 7.8 Hz, 1H, Ph-C3-H), 7.85–7.68 (m, 1H,
Ph-C5-H), 7.35 (t, J = 7.5 Hz, 1H, Ph-C4-H), 7.26 (s, 1H, Py-C3-H),
Entry 7
1H NMR (500 MHz, DMSO-d6)d 8.27 (d, J = 5.1 Hz, 1H, C6-H),
7.20 (d, J = 8.4 Hz, 1H, Ph-C6-H), 6.96 (dd, J = 1.3 and 5.3 Hz, 1H, 7.37–7.35 (m, 1H, C3-H), 7.27–7.23 (m, 1H, C5-H), 2.34 (s, 3H,
Py-C5-H), 5.28 (s, 2H, CH2), 2.71 (d, J = 4.6 Hz, 3H, urea-CH3).
CH3).
J. Label Compd. Radiopharm 2009, 52 376–381
Copyright r 2009 John Wiley & Sons, Ltd.
www.jlcr.org

S. C. Schou
Table 5. Incorporation of deuterium observed using different rhodium sources
Entry
Rhodium source
%D
10.5 eq. Crabtree’s catalyst, %D
1
2
3
4
5
6
7
8
Rh black (Alfa Aesar)
Rh black (ABCR)
Rh black (Aldrich)
Rh (Acros)
19
16
16
0
93
50–57
91
0
0
90
Rh (Fluka)
0
5wt% Rh/act. aluminaa
5wt% Rh/aluminaa
5wt% Rh/carbona
75–92
71
88
93
85
aAdded amount correlates to 0.6 eq. rhodium. Experimental conditions: 1 (0.016 mmol), catalyst/catalysts, dry THF:DCM
(1:1)(3 mL), D2 (1550–1665 mbar), RT, 4 h.
4.0 Hz, 1H, C5-H), 7.34 (dd, J = 4.6 and 8.5 Hz, 1H, C4-H), 3.83
(s, 3H, OCH3).
Table 6. Incorporation of deuterium observed in different
solvents
Entry 14
1H NMR (600 MHz, DMSO-d6)d 8.70 (s, 1H, C2-H), 8.51 (s, 1H, C4-H).
Entry 15
% incorporation of deuterium
Entry
Solvent
No additive
10.5 e.q Crabtree’s
catalyst
1H NMR (600 MHz, DMSO-d6)d 7.04–6.94 (m, 2H, C3,5-H), 6.55
(dd, J = 5.5 and 13.1 Hz, 2H, C2,6-H), 6.48 (t, J = 7.3 Hz, 1H, C4-H),
4.98 (s, 2H, NH2).
1
2
3
4
5
Et2O
EtOAc
DCM
THF
0a
84
60
89
90–93c
Conclusion
A new catalytic system based on rhodium black with Crabtree’s
catalyst as an additive has been investigated. In general, the
mixture has an improved activity, compared with rhodium black
alone. In two cases neither Crabtree’s catalyst nor rhodium black
was able to promote exchange, but using the mixture an
incorporation of deuterium was observed. The new catalytic
system is active in a variety of solvents, extending the
usefulness. This protocol will, of course, also be useful when
tritiated compounds are needed. The scope of this new catalytic
system is currently being investigated further in our laboratories.
THF:DCM (1:1)
16b
a1 is slightly soluble in Et2O.
bExperiment performed in THF-d8:DCM-d2 show a similar
incorporation level (12%).
cExperiment performed in THF-d8:DCM-d2 show a slightly
decreased incorporation level (68%). Experimental condi-
tions: 1 (0.016 mmol), catalyst/catalysts, dry THF:DCM
(1:1)(3 mL), D2 (1418–1666 mbar), RT, 4 h.
Entry 8
Acknowledgement
1H NMR (500 MHz, DMSO-d6)d 8.64 (d, J = 5.0 Hz, 1H, C6-H),
7.88 (d, J = 1.0 Hz, 1H, C2-H), 7.85 (dd, J = 1.2 and 3.5 Hz, 1H,
C5-H), 3.91 (s, 3H, OCH3).
The author gratefully thanks Gunnar Grue-Sørensen (LEO
Pharma) for fruitful discussions and invaluable assistance
and support, the Department of Spectroscopy and Physical
Chemistry at LEO Pharma, especially Grethe Aagaard for NMR
assistance and Lone Møss and Else Kristoffersen for obtaining
high resolution NMR-spectra.
Entry 9
1H NMR (500 MHz, DMSO-d6)d 8.85 (dd, J = 1.6 and 4.4 Hz, 2H,
C2,6-H), 7.87 (dd, J = 1.7 and 4.4 Hz, 2H, C3,5-H).
Entry 10
1H NMR (600 MHz, DMSO-d6)d 8.69 (ddd, J = 1.0, 1.8 and
4.8 Hz, 1H, C6-H), 8.10 (dt, J = 1.8 and 3.2 Hz, 2H, Ph-C2,6-H), 7.97
(dt, J = 1.0 and 8.0 Hz, 1H, C4-H), 7.89 (td, J = 1.8 and 7.8 Hz, 1H,
C3-H), 7.54–7.48 (m, 2H, Ph-C3,5-H), 7.47–7.42 (m, 1H, Ph-C4-H),
7.36 (ddd, J = 1.1, 4.8 and 7.4 Hz, 1H, C5-H).
Entry 11
References
1H NMR (500 MHz, DMSO-d6)d 8.49 (dd, J = 0.8 and 4.8 Hz, 1H,
C6-H), 7.69 (td, J = 1.9 and 7.7 Hz, 1H, C4-H), 7.25 (t, J = 7.8 Hz, 1H,
C5-H), 7.18 (ddd, J = 1.1, 4.8 and 7.4 Hz, 1H, C3-H), 3.01 (hept,
J = 6.9 Hz, 1H, i-Pr-CH), 1.23 (d, J = 6.9 Hz, 6H, i-Pr-CH3).
Entry 12
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1H NMR (500 MHz, MeOD)d 8.19 (s, 1H, C6-H), 7.66 (d,
J = 7.2 Hz, 1H, C4-H), 7.10 (d, J = 8.4 Hz, 1H, C3-H), 6.99–6.92 (m,
1H, C5-H).
Entry 13
1H NMR (500 MHz, DMSO-d6)d 8.31 (d, J = 2.9 Hz, 1H, C3-H),
8.18 (dd, J = 1.3 and 4.5 Hz, 1H, C6-H), 7.38 (ddd, J = 1.2, 2.2 and
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S. C. Schou
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2005054179 A2.
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www.jlcr.org