Iridium-catalyzed H/D exchange at vinyl groups without olefin isomerization

Article abstract of DOI:10.1002/anie.200801992

(Chemical Equation Presented) Making the switch: The title reaction represents a rare example of olefinic C-H activation without olefin isomerization. The conditions are sufficiently mild so that functional groups such as ketones, esters, nitriles, amines, sulfides, and alcohols are tolerated. This selectivity is demonstrated by deuterium labeling of several complex molecules.

Full text of DOI:10.1002/anie.200801992

Angewandte
Chemie
DOI: 10.1002/anie.200801992
À
C H Activation
Iridium-Catalyzed H/D Exchange at Vinyl Groups without Olefin
Isomerization**
Jianrong Zhou and John F. Hartwig*
Exchange of a hydrogen atom with a deuterium atom (H/D
isomerization. This selectivity, along with high functional
group compatibility, is demonstrated by H/D exchange
between C6D6 and a series of olefins containing various
functional groups, as well as natural products and natural
product analogues.
The discovery of this H/D exchange chemistry resulted
from studies with the amidoiridium hydride complex
[(dtbpp)Ir(H)(NH2)] (1) (dtbpp = 1,5-bis(di-tert-butylphos-
phino)pentan-3-yl) [Eq. (1)], that we had previously shown
to form by oxidative addition of ammonia.[14] The reaction of
pentene in C6D6 in the presence of catalytic amounts of 1 led
to rapid H/D exchange of the olefinic hydrogen atoms with
the C6D6 solvent. No isomerization of the olefin was
observed, and less than 1% deuterium was incorporated
into the alkyl chain, including the allylic positions.
À
exchange) was one of the first catalytic C H activation
processes reported to occur by organometallic intermedi-
ates.[1] This process has experienced a renaissance recently
because of the value of deuterated and tritiated compounds in
the study of reaction mechanisms and biological processes.[2]
In general, deuterium or tritium can be introduced during a
synthesis with a deuterated or tritiated reagent, or after the
synthesis is complete by H/D or H/T exchange. If regio- and
stereoselective H/D or H/Texchange could be developed, the
latter approach would be simpler to conduct and more cost
effective than the introduction of the label during synthesis.
Moreover, it would avoid the handling of tritiated synthetic
intermediates.[3]
H/D exchange of aromatic hydrogen atoms is well known
and has been conducted with a variety of catalysts, including
acid, base, and metal complexes.[4] H/D exchange of non-
À
activated, aliphatic C H bonds has also been conducted with
transition-metal catalysts,[5] including [Cp*Ir(PMe3)],[6,7]
[Cp*Ir(carbene)],[8] and [(TpMe2)Ir] complexes.[9] H/D
exchanges catalyzed by the recently developed systems
afford a high degree of isotope incorporation, and some
have been conducted with D2O as the deuterium source.[10]
In contrast to H/D exchange at aryl and alkyl groups, H/D
exchange at vinyl groups has not been studied extensively.
Most existing examples of H/D exchange at vinyl groups have
been conducted with cyclic or isolated olefins, such as
cyclopentene, styrene, and tert-butylethylene, presumably to
avoid complications from olefin isomerization.[8,11] A more
general, selective H/D exchange of alkene hydrogen atoms
has been limited because alkene isomerization often occurs
On the basis of this observation, a series of catalysts were
evaluated for H/D exchange between C6D6 and 5-hexenyl
acetate (Table 1). This substrate was chosen for the evaluation
of catalysts because it would reveal the relative rates for H/D
exchange at olefinic positions and at enolizable hydrogen
atoms that are known to undergo H/D exchange in the
presence of iridium catalysts.[6,8] Complex
1 catalyzed
À
under conditions that lead to C H activation. For example, H/
exchange at the olefinic positions faster than at the acetate.
D exchange of 1-pentene[12] and 1-hexene[6,13] has caused
isomerization to the more stable internal isomers at elevated
temperature,[6] at room temperature,[12] and under photo-
chemical conditions.[13] We report a catalytic system that
overcomes this limitation. We show that H/D exchange
catalyzed by an iridium complex containing an aliphatic
pincer ligand occurs at the vinylic positions without olefin
Table 1: Selectivity pattern of H/D exchange catalysts (percentage of
deuterium incorporation).
=
CD C
=
C CD2
Entry
Catalyst
Conditions
a-CD3
1
2
3
4
5
6
7
8
1
2
3
3
4
4
5
5
RT, 10 h
RT, 10 h
RT, 3 h
RT, 10 h
RT, 10 h
508C, 8 h
RT, 10 h
508C, 8 h
23
37
32
74
0
0
0
0
87
96
0
2
0
0
30
45
94
98[a]
52
[*] J. Zhou, Prof. J. F. Hartwig
Department of Chemistry
61
University of Illinois Urbana-Champaign
600 South Matthews Ave, Box 58-6, Urbana, IL 61801 (USA)
Fax: (+1)203-432-6144
0[b]
0[b]
6[c]
E-mail: jhartwig@uiuc.edu
21[d]
[**] We thank the DOE for support of this work andJohnson-Matthey for
a gift of iridium.
[a] 11% hydrogenation byproduct. [b] 8% hydrogenation byproduct.
[c] 4% hydrogenation byproduct. [d] 5% hydrogenation byproduct and
8% olefin isomers.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801992.
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The distribution of products generated by tetrahydride 2 was
similar to that produced by amido complex 1, presumably
because these two complexes react through the same active
achieved with only 0.5 mol% of 1, although a longer reaction
time was required. Incorporation of 96% deuterium into the
internal vinylic position of 1-pentene required about 20 hours
with 5 mol% of 1. H/D exchange of olefins containing amine,
ester, and nitrile groups occurred at rates that were similar or
slightly slower than those for H/D exchange of 1-pentene.
H/D exchange of the olefinic hydrogen atoms of
unstrained 1,1-disubstituted and cis-1,2-disubstituted olefins
with C6D6 proceeded more slowly than with the vinylic
hydrogen atoms of 1-pentene, but exchange did occur
selectively. For example, 84% deuterium incorporation
occurred exclusively at the vinyl position of cyclohexene
after 50 hours at 508C. H/D exchange of the olefinic hydrogen
atoms of the strained norbornene was faster. H/D exchange of
norbornene with [D6]benzene led to 92% deuterium incor-
poration into the olefinic positions within 3 hours at room
temperature.[16] H/D exchange with trans-1,2-disubstituted
olefins did not occur. Thus, selective labeling of trans-hexa-
1,4-diene was observed at the terminal double bond.
catalyst. In contrast to the iridium catalysts, rhodium ana-
logue 3 reacted with both the terminal olefinic hydrogen
atoms faster than at the internal hydrogen atoms, and it led to
exchange of the enolizable hydrogen atoms.
Although iridium complexes with aromatic pincer ligands
readily activate aliphatic hydrogen atoms at elevated temper-
atures, H/D exchange at room temperature catalyzed by
aromatic pincer complexes 4 and 5[15] was much slower than
that catalyzed by 1–3. Because of the high reactivity of 1, a
majority of studies on the selectivity with substrates contain-
ing other functional groups were conducted with this catalyst.
Results of H/D exchange of different classes of olefins
catalyzed by complex 1 are summarized in Figure 1. The
In addition to the selectivity for exchange at different
À
olefinic C H bonds, the method was compatible with many
functional groups. As shown in Table 1 and Figure 1, these
functional groups include nitriles, primary amines, unpro-
tected alcohols, esters, and ketones. When acidic hydrogen
atoms a to the functional group were present, such as those in
nitrile and ester groups, partial H/D exchange with these
À
hydrogen atoms was observed. Unactivated, aliphatic C H
bonds did not react.
Complex 1 also catalyzed H/D exchange between C6D6
and substituted aromatic and heteroaromatic compounds
(Figure 2). The regioselectivity of H/D exchange was con-
Figure 2. Percentage of deuterium incorporation into aromatic and
heteroaromatic substrates catalyzedby 5 mol% 1 in C6D6.
Figure 1. Percentage of deuterium incorporation into olefinic sub-
strates catalyzedby 5 mol% 1 in C6D6.
trolled by steric effects. For example, nearly complete H/D
exchange was observed after 1 h at room temperature at the
mutually meta position of 1,3-dibromobenzene, but negligible
H/D exchange was observed at the position ortho to both
bromines. Many heteroaromatic substrates, including substi-
tuted furans, thiophenes, pyrroles, and imidazoles also under-
went deuteration. Even pyridine, which has been reported to
deactivate several other iridium catalysts toward H/D
exchange,[6,9] underwent H/D exchange catalyzed by 1.
The functional group tolerance and selectivity shown by
the results in Figure 1 suggested that selective H/D exchange
could be conducted at the vinylic positions of complex
molecules. Results on H/D exchange between [D6]benzene
efficiency of exchange for individual hydrogen atoms
depended strongly on the steric environment. For example,
exclusive and nearly complete deuteration at the terminal,
trans position of the tert-butylethylene was achieved after
1 minute at room temperature,[12] but facile exchange was
observed at similar rates with the more accessible trans and
cis-terminal hydrogen atoms of vinyltrimethylsilane. Like-
wise, the reaction of 1-pentene led to the exchange of more
than 90% of the trans terminal hydrogen atom after
5 minutes at room temperature, whereas less than 10% of
the exchange occurred at each of its cis terminal and internal
positions. A similar level of deuteration of 1-pentene was
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and two natural products and one synthetic steroid are shown
in Figure 3. Brief exposure of tiamulin to catalyst 1 in C6H6
led to selective labeling of one of the terminal olefinic
Figure 4. ORTEP diagram of 7 (thermal ellipsoids are set at 20%
probability, andmethyl groups have been omittedfor clarity).
Figure 3. H/D Exchange of vinylic hydrogen atoms in complex mole-
cules (percentage of deuterium incorporation).
The equilibrium shown in Equation (3) was established within
5 minutes at room temperature. However, the H/D exchange
of [D6]benzene with tert-butylethylene, catalyzed by 7, was
slower than the reaction catalyzed by 1 (Figure 5). This result
implies that olefin complex 7 is not the complex that catalyzes
the majority of the H/D exchange of tert-butylethylene.
hydrogen atoms. Exchange of the trans hydrogen atom was
more than an order of magnitude faster than exchange of the
cis hydrogen atom. Similar rapid H/D exchange of the olefin
of forskolin occurred almost exclusively at the trans position.
Likewise, H/D exchange of the three hydrogen atoms of the
terminal olefin of altrenogest occurred over 20 hours. In each
case, no detectable H/D exchange was observed by 2H, 1H or
13C NMR spectroscopy at the internal olefins, and no isomer-
ization of the terminal olefin to internal isomers was observed
by 1H or 13C NMR spectroscopy.
To shed light on the mechanism of the H/D exchange
process, we monitored the catalytic reaction by using 5 mol%
of amide complex 1 by 31P NMR spectroscopy. The resting
state of the catalyst in the H/D exchange of [D6]benzene with
1-pentene was approximately a 1:2 mixture of amide 1 and
[(dtbpp)Ir(1-pentene)] (6). However, in the reaction of
[D6]benzene with tert-butylethylene, the resting state was
=
approximately a 4:1 mixture of 1 and [{(tBu)2PCH2CH2CH
Figure 5. Comparison of catalysts 1 and 7 in H/D exchange of tert-
CHCH2P(tBu2)}IrPh] (7). Iridium complex 7, containing an
olefin in the backbone bound to the metal, was prepared
independently by the reaction of [(dtbpp)IrH4] with norbor-
nene in benzene [Eq. (2)], and its structure was determined
by X-ray crystallography.[17] The structure of 7 is shown in
Figure 4. The olefin on the dehydrogenated ligand[18] is bound
to the iridium in an h2 manner, and the coordination geometry
around the metal is best described as square planar.
butylethylene in C6D6.
Instead, we conclude that the H/D exchange occurs by a
mechanism in which the methine position of the backbone
acts as a shuttle. This proposal is supported by the observation
of deuterium incorporation into that position in amide 1.
Dissolution of 1 in [D6]benzene led to the growth of a
2H NMR signal at 2.5 ppm corresponding to the backbone
methine hydrogen atom in 1. The same deuterium signal was
also detected during H/D exchanges of [D6]benzene with 1-
pentene and tert-butylethylene catalyzed by 5 mol% of amide
complex 1. This intimate participation of the central hydrogen
atom on the aliphatic backbone of the pincer ligand explains
why iridium complex 4, containing an aromatic ligand, does
not catalyze these H/D exchanges under similarly mild
conditions.[19]
Backbone olefin complex 7 underwent reversible H/D
exchange between [D6]benzene and the olefinic position that
was originally the central carbon atom of the backbone in 1.
Two potential mechanisms in which the methine hydrogen
atom acts as a shuttle are outlined in Scheme 1. In the first
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[1] J. L. Garnett, R. J. Hodges, J. Am. Chem. Soc. 1967, 89, 4546.
[2] a) Synthesis and Applications of Isotopically Labeled Com-
pounds, Vol. 7 (Eds.: U. Pleiss, R. Voges), Wiley, New York,
2001; b) T. H. Lowry, K. S. Richardson, Mechanism and Theory
in Organic Chemistry, Harper & Row, New York, 1987; c) A. F.
Thomas, Deuterium Labeling in Organic Chemistry, Appleton-
Century-Crofts, New York, 1971.
[3] a) T. Junk, W. J. Catallo, Chem. Soc. Rev. 1997, 26, 401; b) M.
Saljoughian, P. G. Williams, Curr. Pharm. Des. 2000, 6, 1029;
c) M. Saljoughian, Synthesis 2002, 1781; d) J. Atzrodt, V. Derdau,
T. Fey, J. Zimmermann, Angew. Chem. 2007, 119, 7890; Angew.
Chem. Int. Ed. 2007, 46, 7744; e) J. R. Heys, J. Labelled Compd.
Radiopharm. 2007, 50, 770; f) W. J. S. Lockley, J. Labelled
Compd. Radiopharm. 2007, 50, 779.
[4] a) Q. X. Guo, B. J. Shen, H. Q. Guo, T. Takahashi, Chin. J. Chem.
2005, 23, 341; b) H. Sajiki, N. Ito, H. Esaki, T. Maesawa, T.
Maegawa, K. Hirota, Tetrahedron Lett. 2005, 46, 6995, and
references cited therein.
[5] a) J. L. Garnett, R. S. Kenyon, J. Chem. Soc. D 1971, 1227;
b) A. E. Shilov, A. A. Shteinman, Coord. Chem. Rev. 1977, 24,
97.
[6] C. M. Yung, M. B. Skaddan, R. G. Bergman, J. Am. Chem. Soc.
2004, 126, 13033.
[7] a) M. B. Skaddan, C. M. Yung, R. G. Bergman, Org. Lett. 2004,
6, 11; b) S. R. Klei, T. D. Tilley, R. G. Bergman, Organometallics
2002, 21, 4905; c) S. R. Klei, J. T. Golden, T. D. Tilley, R. G.
Bergman, J. Am. Chem. Soc. 2002, 124, 2092; d) J. T. Golden,
R. A. Andersen, R. G. Bergman, J. Am. Chem. Soc. 2001, 123,
5837.
[8] R. Corberµn, M. Sanaffl, E. Peris, J. Am. Chem. Soc. 2006, 128,
3974.
[9] L. L. Santos, K. Mereiter, M. Paneque, C. Slugovc, E. Carmona,
New J. Chem. 2003, 27, 107.
[10] a) M. Yamamoto, K. Oshima, S. Matsubara, Heterocycles 2006,
67, 353; b) T. Kurita, K. Hattori, S. Seki, T. Mizumoto, F. Aoki, Y.
Yamada, K. Ikawa, T. Maegawa, Y. Monguchi, H. Sajiki, Chem.
Eur. J. 2008, 14, 664, and references cited therein.
[11] a) B. Rybtchinski, R. Cohen, Y. Ben-David, J. M. L. Martin, D.
Milstein, J. Am. Chem. Soc. 2003, 125, 11041; b) C. P. Lenges,
P. S. White, M. Brookhart, J. Am. Chem. Soc. 1999, 121, 4385;
c) J. Krüger, B. Manmontri, G. Fels, Eur. J. Org. Chem. 2005,
1402.
[12] a) J. W. Faller, C. J. Smart, Organometallics 1989, 8, 602; b) J. W.
Faller, H. Felkin, Organometallics 1985, 4, 1488.
[13] G. Kohl, R. Rudolph, H. Pritzkow, M. Enders, Organometallics
2005, 24, 4774.
[14] We have reported the synthesis of 1 by the oxidative addition of
ammonia to the corresponding [(dtbpp)Ir(olefin)] complexes: J.
Zhao, A. S. Goldman, J. F. Hartwig, Science 2005, 307, 1080.
[15] a) M. Gupta, C. Hagen, R. J. Flesher, W. C. Kaska, C. M. Jensen,
Chem. Commun. 1996, 2083; b) M. Gupta, C. Hagen, W. C.
Kaska, R. E. Cramer, C. M. Jensen, J. Am. Chem. Soc. 1997, 119,
840; c) F. C. Liu, E. B. Pak, B. Singh, C. M. Jensen, A. S.
Goldman, J. Am. Chem. Soc. 1999, 121, 4086.
[16] C. Slugovc, B. Perner, Inorg. Chim. Acta 2004, 357, 3104.
[17] CCDC-686286 (7) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
Scheme 1. Proposedpathways for the iridium-catalyzedH/D exchange
in C6D6.
mechanism, the iridium(I) fragment, [(dtpbb)IrI], generated
by reductive elimination of NH3 and dissociation of the olefin
from resting states 1 and 6, could undergo oxidative addition
À
of the aryl hydrogen atom and subsequent reversible C H
reductive elimination involving the methine carbon center on
the ligand to form aryl iridium(I) complex 8.[20] Alternatively,
the complex resulting from oxidative addition of the arene
could undergo reversible a-hydrogen elimination from the
ligand backbone to generate iridium(III) carbene 9.[21] We
favor the reductive elimination pathway in Scheme 1 because
of the facility of reductive elimination of alkanes from alkyl
hydride complexes relative to a-hydrogen elimination from
low-valent metal complexes. A parallel process with the
À
vinylic C H bonds would lead to incorporation of deuterium
into the olefinic substrates.
In summary, selective deuteration of alkenes occurs in the
presence of iridium catalysts containing an aliphatic pincer
ligand. These reactions occur with reagents bearing a variety
of auxiliary functionality without isomerization of the olefin,
and these properties enable selective labeling of olefins in
complex molecules. Additional studies on the mechanism of
this process and reactions catalyzed by rhodium analogue 3
will be subjects of future studies.
Experimental Section
In an argon-filled glove box, a screw-capped NMR tube was charged
with iridium catalyst 1 (5.6 mg, 0.010 mmol), C6D6 (0.50 mL), and 1-
pentene (14 mg, 0.20 mmol). The tube was tightly capped and then
vigorously shaken to give an orange solution. After 5 min at room
temperature, the reaction mixture was exposed to air and passed
through a short plug of silica gel with C6D6 washings to remove
iridium complexes. The filtrate was judged to be pure by 1H and
13C NMR spectroscopy. The percentage of H/D exchange was based
on a decrease in the integral of the 1H NMR signals, as compared to
the integral of the corresponding signals in the starting material. The
1H NMR signals of interest were integrated relative to the resonance
for allylic hydrogen atoms that do not undergo H/D exchange. The
position of deuterium incorporation was also confirmed by 2H NMR
spectroscopy. The same reaction was conducted with 1 mmol 1-
pentene in 2.5 mL of C6D6 with 5 mol% catalyst 1, and a similar
degree of H/D exchange was observed.
[18] Complexes containing a dehydrogenated dtbpp ligand have been
reported for rhodium and ruthenium: a) D. G. Gusev, A. J.
Lough, Organometallics 2002, 21, 2601; b) C. Crocker, R. J.
Errington, R. Markham, C. J. Moulton, K. J. Odell, B. L. Shaw, J.
Am. Chem. Soc. 1980, 102, 4373.
Received: April 28, 2008
Published online: June 24, 2008
À
Keywords: alkenes · C H activation · deuterium · iridium ·
isomerization
[19] For H/D exchange of arenes by ruthenium and iridium catalysts
containing pincer ligands, see a) A. Trꢀff, G. N. Nilsson, K. J.
.
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Szabo, L. Eriksson, J. Organomet. Chem. 2007, 692, 5529;
b) M. H. G. Prechtl, M. Hꢁlscher, Y. Ben-David, N. Theyssen, R.
Loschen, D. Milstein, W. Leitner, Angew. Chem. 2007, 119, 2319;
Angew. Chem. Int. Ed. 2007, 46, 2269.
[21] a-Hydrogen elimination to form iridium–carbene complexes is
known: a) H. D. Empsall, E. M. Hyde, R. Markham, W. S.
McDonald, M. C. Norton, B. L. Shaw, B. Weeks, J. Chem. Soc.
Chem. Commun. 1977, 589; b) E. Carmona, M. Paneque, L. L.
Santos, V. Salazar, Coord. Chem. Rev. 2005, 249, 1729; c) E. Clot,
J. Chen, D. H. Lee, S. Y. Sung, L. N. Appelhans, J. W. Faller,
R. H. Crabtree, O. Eisenstein, J. Am. Chem. Soc. 2004, 126, 8795.
[20] a) M. A. McLoughlin, R. J. Flesher, W. C. Kaska, H. A. Mayer,
Organometallics 1994, 13, 3816; b) A. Vigalok, Y. Ben-David, D.
Milstein, Organometallics 1996, 15, 1839.
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