The mediation of aryl ketone deuteration by [Ir(PPh3) 3(cod)]+.BF4-

Article abstract of DOI:10.1002/jlcr.925

The usefulness of the hydrogen isotope exchange catalyst, [Ir(PPh ₃)₃(cod)]⁺.BF₄^- (1), is explored. It appears that isotopic exchange mediated by 1 occurs via a series of complexes in which all three phosphine ligands are retained. The disadvantage of this system is that the catalytic intermediates are necessarily sterically hindered, with the result that the range of substrates for which the system is effective is small. Copyright

Full text of DOI:10.1002/jlcr.925

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 317–322.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.925
Research Article
The mediation of aryl ketone deuteration
by [Ir(PPh3)3(cod)]+.BF4ꢀ
John M. Herbert*
´
Isotope Chemistry and Metabolite Synthesis Department, sanofi-aventıs, Willowburn
Ave., Alnwick, Northumberland NE66 2JH, UK
Summary
The usefulness of the hydrogen isotope exchange catalyst, [Ir(PPh3)3(cod)]+.BF4ꢀ (1),
is explored. It appears that isotopic exchange mediated by 1 occurs via a series of
complexes in which all three phosphine ligands are retained. The disadvantage of
this system is that the catalytic intermediates are necessarily sterically hindered, with
the result that the range of substrates for which the system is effective is
small. Copyright # 2005 John Wiley & Sons, Ltd.
Key Words: iridium tris(phosphine) complexes; isotope exchange; ortho-deuteration
Introduction
In the process of establishing conditions for iridium-mediated hydrogen
isotope exchange with a range of aromatic substrates, it was found that the
putative pre-catalyst, (cyclooctadiene)tris(triphenylphosphine) iridium(I) tet-
rafluoroborate (1) was unexpectedly efficient in promoting exchange in
acetophenone, resulting in essentially quantitative displacement of the ortho-
protons (Scheme 1).1 In the light of this result, further work was undertaken,
′
′
Scheme 1. ortho-Deuteration of aryl ketones in the presence of 1
both to examine the more general utility of this complex as a catalyst for
isotope exchange in aryl ketones and in the hope of better understanding the
*Correspondence to: Dr J. M. Herbert, Isotope Chemistry and Metabolite Synthesis Department,
sanofi-aventı
´
sanofi-aventı
´
s, Willowburn Ave., Alnwick, Northumberland NE66 2JH, UK. E-mail: john.herbert@
s.com
Copyright # 2005 John Wiley & Sons, Ltd.
Received 29 October 2004
Revised 16 December 2004
Accepted 17 December 2004

318
J. M. HERBERT
mechanism by which exchange works with this and other complexes. This
work is the subject of this publication.
Results and discussion
Given the robustness of the catalyst formed from 1, it is relevant to consider
the mechanism by which it mediates exchange. When NMR spectra of a 1:1
mixture of 1 and acetophenone were recorded 1 h after exposure to hydrogen,
the 1H spectrum contained resonances consistent with the presence of
cyclooctane and cyclooctene in a ratio of approximately 1:1.2. The substrate
methyl protons gave rise to a broad singlet centred at d 2.50, consistent with
the presence of several closely related (and presumably isomeric) bound forms
of acetophenone; there was no signal attributable to free acetophenone. The
aromatic envelope was complex but did contain identifiable signals
corresponding to the protons of variously bound forms of acetophenone.
Even after 120 h, the spectrum was essentially unchanged, apart from the near-
disappearance of peaks due to cyclooctene. Upfield signals were complex but
occurred in two clear clusters around d ꢀ 24 and around d ꢀ 11, the former
being very minor; these are consistent with metal hydride and metal
dihydrogen species, respectively. Whereas the 31P NMR spectrum of 1
contains only one signal,1 due to rapid Berry pseudo-rotation as reported
previously,2 the corresponding hydrogenated acetophenone complex gives rise
to a number of distinct resonances between d ꢀ 1 and +22. However, what is
noticeably absent in the 31P spectrum is any signal due to free triphenylpho-
sphine (observed at d ꢀ 3:83 under the same conditions), all the signals
observed being downfield of this point. The implication is that all of these
signals correspond to metal-bound phosphines in different environments.
Possibly the most instructive feature of the NMR spectra is the
predominance of signals (in the 1H spectrum) arising from bound dihydrogen,
rather than hydride. In the accepted mechanism of exchange using
Ir(cod)(PPh3)+2 .BF4ꢀ (2) and its analogues (Scheme 2),3 the complex bears at
least one hydride ligand at all stages. Since the various species formed upon
hydrogenation of 1 in the presence of acetophenone appear to contain more
bound dihydrogen than hydride, and free triphenylphosphine does not appear
to be liberated, it appears likely that the mechanism operating is the same, but
with a third phosphine in place of hydride in each intermediate (Scheme 2).
Scheme 2. Key intermediates in isotopic exchange mediated by 1 (X=PPh3) and
2 (X=D)
Copyright # 2005 John Wiley & Sons, Ltd.
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THE MEDIATION OF ARYL KETONE DEUTERATION
319
Table 1. Deuteration of aryl ketones mediated by 1 and 2a
R
R0
1 (C2/C6)
2 (C2/C6)1
H
H
3-Cl
4-Cl
4-Br
3-Me
4-Me
3-OMe
4-OMe
4-cyclohexyl
Me
Ph
Me
Et
Me
Me
Pr
Me
i-Pr
Me
1.0/1.01
0.8/0.8
0.35/0.35
0.67/0.82
0.90/0.90
0.88/0.88
0.54/0.59
0.94/0.94
0.35/0.85
0.35/0.35
0.83/0.83
0.95/0.95
0.9/1.0
0.85/0.85
a Figures are the number of deuterium atoms per molecule of substrate, at the positions indicated, as
determined by 1H NMR spectrometry.
The presence of very small quantities of a bis(triphenylphosphine) species,
which could be the active intermediate, cannot be discounted entirely on
the basis of the NMR data. However, indirect evidence that the active
species retains all three phosphine ligands comes from efforts to examine
the scope and limitations of 1 in exchange into a range of simple ketones
(Table 1). Since the intermediates formed from 1 are sterically encumbered
by comparison to those involved in the process mediated by 2, it was expected
that hindered ketones would be poorer exchange substrates. In exchange
processes mediated by Ir(cod) (Py) (PCy3) þ .PF6-(3), steric hindrance results
most obviously in the blocking of exchange (in benzamides) between a
directing group and a meta-substituent.4 With 1, not only does the same effect
occur in the deuteration of meta-substituted ketones, but levels of exchange at
C6 in these cases are reduced by comparison with those observed in para-
substituted substrates. Moreover, even a bulky para-substituent reduces the
extent of exchange slightly, as in the case of 40-cyclohexylacetophenone. In
contrast, exchange processes mediated by 2 are largely unaffected by meta
substituents.1 Moreover, the presence of any substituent a- to the directing
carbonyl has an even greater disruptive effect on the exchange process; the
tolerance of a-branching is very much poorer than with 3, which mediates
incorporation of 1.0D into 4-methoxyisobutyrophenone and 1.85D into
desoxybenzoin. The range of substrate geometry over which 1 operates
effectively is rather limited also: phenylacetone incorporates 0.2D, but
1-indanone, where formation of a geometrically constrained five-membered
metallacycle would be required, is not exchanged at all.
In summary, exchange mediated by complex 1 results from a variation upon
the accepted mechanism for such processes. The presence of a third phosphine
results in stabilization of the hydrogenated complex in the absence of an excess
of ligand, so that exchange proceeds to completion for sterically unencum-
bered substrates.
Copyright # 2005 John Wiley & Sons, Ltd.
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J. M. HERBERT
Experimental
Analytical methods were as described previously.1,4 Bis(1,5-cyclooctadiene)-
diiridium(I) dichloride was obtained from Strem. 4-Methoxyisobutyrophe-
none was prepared by Friedel-Crafts acylation of anisole.5
Typical exchange procedure
A suspension of silver tetrafluoroborate (20 mg) in DCM (10 ml) containing
bis(1,5-cyclooctadiene)diiridium(I) dichloride (40 mg, 60 mmol) and triphenyl-
phosphine (94 mg, 0.36 mmol), was stirred for 20–30 min under nitrogen,
then filtered through Celite. The pad was washed through with DCM until
the filtrates became clear, and the combined filtrates were made up to 12 ml
with DCM, to give a 10 mmol/ml solution of 1. This solution (1 ml/20 mmol)
was added to the substrate; the system was degassed and flushed with
deuterium, then sealed and stirred for 66–68 h. After this time most of
the volatiles were evaporated and the product was isolated by preparative t.l.c
on silica gel.
Selected product data are summarized below
Exchange of 1-(4-methylphenyl)-1-butanone (22 mg, 0.13 mmol) in the
presence of 1 (0.06 mmol) gave [benzene-2,6-2H2]-1-(4-methylphenyl)-1-buta-
none (16 mg, 73%). dH(CDCl3) 0.98 (3H, t, J=7.3 Hz), 1.75 (2H, observed as
sextet, J=7.3 Hz), 2.39 (3H, s), 2.89 (2H, t, J=7.3 Hz), 7.23 (2H, s), 7.84
(0.12H, d, J=8.3 Hz); m/z 134, 133 (M+), 105, 104 ([M-C2H5]+).
Exchange of 1-(4-chlorophenyl)-1-propanone (17 mg, 0.1 mmol) in the
presence of 1 (0.05 mmol) as above gave [benzene-2,6-2H2]-1-(4-chlorophe-
nyl)-1-propanone (13 mg, 76%). dH(CDCl3) 1.20 (3H, t, J=7.2 Hz), 2.96 (2H,
q, J=7.2 Hz), 7.31 (1H, m), 7.41 (2H, s), 7.88 (0.12H, d, J=8.9 Hz); m/z 172,
170 (M+), 143, 141 (100%, [M-CH3]+).
Exchange of 3-chloroacetophenone (39 ml, 0.3 mmol) in the presence of 1
(0.15 mmol) gave [benzene-2,6-2H2]-3-chloroacetophenone (32 mg, 68%).
dH(CDCl3) 2.59 (3H, s), 7.53–7.57 (1H, m), 7.69 (1H, d, J=8.1 Hz), 7.89
(0.33H, dd, J=7.6, 1.2 Hz), 7.92–7.93 (0.18H, m); m/z 156, 155 (M+), 142,
141, 140 (100%, [M-CH3]+).
Exchange of 3-methylacetophenone (40 ml, 0.3 mmol) in the presence of 1
(0.15 mmol) gave [benzene-2,6-2H2]-3-methylacetophenone (38 mg, 92%).
dH(CDCl3) 2.37 (3H, s), 2.55 (3H, s), 7.38–7.41 (1H, m), 7.44 (1H, d,
J=7.3 Hz), 7.74 (0.41H, d, J=7.4 Hz), 7.76 (0.46 H, s); m/z 136, 135, 134
(M+), 121, 120, 119 (100%, [M-CH3]+).
Exchange of 3-methoxyacetophenone (42 ml, 0.3 mmol) in the presence of 1
(0.15 mmol) gave [benzene-2,6-2H2]-3-methoxyacetophenone (29 mg, 64%).
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THE MEDIATION OF ARYL KETONE DEUTERATION
321
dH(CDCl3) 2.56 (3H, s), 3.81 (3H, s), 7.19 (1H, d, J=8.3 Hz), 7.41–7.45
(1.15H, m), 7.54 (0.65 H, dd, J=7.5, 0.8 Hz); m/z 152, 151 (M+), 137, 136
(100%, [M-CH3]+).
Exchange of 4-bromoacetophenone (12 mg, 0.06 mmol) in the presence of 1
(0.03 mmol) gave [benzene-2,6-2H2]-4-bromoacetophenone (12 mg, 100%).
dH(CDCl3) 2.56 (3H, s), 7.59 (2H, s), 7.79 (0.24H, d, J=8.8 Hz); m/z 199,
200, 201, 202 (M+), 184, 185, 186, 187 ([M-CH3]+), 51 (100%, [M-CH3]+).
Exchange of 4-cyclohexylacetophenone (12 mg, 0.06 mmol) in the presence
of 1 (0.03 mmol) gave [benzene-2,6-2H2]-4-cyclohexylacetophenone (8 mg,
66%). dH(CDCl3) 1.22–1.44 (5H, m), 1.72–1.89 (5H, m), 2.52–2.56 (1H, m),
2.55 (3H, s), 7.28 (2H, s), 7.87 (0.34H, d, J=8.5 Hz); m/z 203, 204, 205 (M+),
188, 189 (100%, [M-CH3]+), 190.
NMR Experiment
A solution of 1 was prepared as described above, from bis(1,5-cyclooctadie-
ne)diiridium(I) dichloride (20 mg, 30 mmol) and triphenylphosphine (47 mg,
180 mmol) in CD2Cl2 (1 ml). Acetophenone (3.6 ml, 30 mmol) was added to half
the solution in an NMR tube, which was then degassed and flushed with
hydrogen. Shaking the solution briefly resulted in discharge of the red colour,
and NMR spectra were recorded after a further 1 h. dH(CD2Cl2) 1.47–1.49 (m,
8H of cyclooctene), 1.52 (s, cyclooctane), 2.10–2.15 (m, 4H of cyclooctene),
2.30–2.70 (br s, 3H of acetophenone), 5.61 (ddd, J=7.2, 5.2, 2.0 Hz, 2H of
cyclooctene), 6.83–7.39 (45H, m), 7.47 (2H, t, J=7.7 Hz), 7.55–7.61 (1H, m),
7.85–7.93 (2H, m), upfield signals not being acquired; dP(CD2Cl2) ꢀ1.04,
ꢀ0.57, 4.88, 5.00, 6.96, 7.92, 11.08, 11.85, 12.29, 14.90 (major), 18.32, 18.56,
21.20, 21.40. After 96 h, the hydrogen atmosphere was replaced by argon, and
after a further 24 h, the spectrum was reacquired: dH(CD2Cl2) ꢀ25.0 to ꢀ24.0
(3 small multiplets, Ir-H), ꢀ23.5 to ꢀ23.0 (3 small multiplets, Ir-H), ꢀ22.2 to
ꢀ21.4 (m, Ir-H), ꢀ12.2 to ꢀ10.8 (m, Ir-H2), ꢀ8.7 to ꢀ8.1 (m, Ir-H2), the
remainder of the spectrum being as above.
Acknowledgements
The author wishes to thank Dr S.J. Byard for the NMR spectra.
References
1. Ellames GJ, Gibson JS, Herbert JM, McNeill AH, Cross PWC, Kerr WJ, Mathers
TW, Trewartha G. Tetrahedron 2003; 59: 3349.
2. Haines LM, Singleton E. J Chem Soc Dalton 1972; 1891.
3. Shu AYL, Heys JR. Organoiridium mediated hydrogen isotope exchange:
observable intermediates in the cyclometalation of [(cod)Ir(PPh3)2]BF4 with
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 317–322

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J. M. HERBERT
benzophenone. In Synthesis and Applications of Isotopically Labelled Compounds,
vol. 6, Heys JR, Melillo DG (eds). Wiley: New York, 1998; 223.
4. Ellames GJ, Gibson JS, Herbert JM, McNeill AH. Tetrahedron 2001; 57: 9487.
5. Encina MV, Lissi EA, Lemp E, Zanocco A, Scaiano JC. J Am Chem Soc 1983; 105:
1856.
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 317–322