Iridium-Catalyzed Formyl-Selective Deuteration of Aldehydes

Article abstract of DOI:10.1002/anie.201702997

We report the first direct catalytic method for formyl-selective deuterium labeling of aromatic aldehydes under mild conditions, using an iridium-based catalyst designed to favor formyl over aromatic C?H activation. A good range of aromatic aldehydes is s

Full text of DOI:10.1002/anie.201702997

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Title: Iridium-catalyzed Formyl-selective Deuteration of Aldehydes
Authors: William John Kerr, Marc Reid, and Tell Tuttle
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Iridium-catalyzed Formyl-selective Deuteration of Aldehydes
William J. Kerr,* Marc Reid, and Tell Tuttle*
Abstract: We report the first direct catalytic method for formyl-
selective deuterium labeling of aromatic aldehydes under mild
conditions, using an iridium-based catalyst designed to favor formyl-
over aromatic C-H activation. A good range of aromatic aldehydes is
selectively labeled, and a one-pot labeling/olefination protocol is also
described. Computational studies support kinetic product control
over competing aromatic labeling and decarbonylation pathways.
trans-oriented bulky ligand pair results in equatorial directing
group binding and consequent aryl C-H activation (Scheme 1,
Path A). We hypothesized, therefore, that a smaller, cis-enabled
ligand pair would facilitate axial aldehyde binding and
subsequent formyl C-H activation (Path B).[5] Importantly, this
proposed ligand-controlled pathway would also avoid the need
for an additional directing group on the aryl ring of the
substrate.[6]
To initiate our studies, we screened a small number of
iridium complexes with large/large and large/small ligand pairs.
Using 2-naphthaldehyde, 1, as a model substrate, we first
examined the large/large ligand partnership, using pre-catalysts
of the type [(COD)Ir(L1)(L2)]PF6, commonly used in ortho-
directed aryl labeling (Scheme 2).[2i,7] In accordance with earlier
stoichiometric tritiation work,[3a,b] the use of Crabtree‘s catalyst,
2,[8] led to appreciable levels of labeling across both the aromatic
and formyl positions. Remarkably, employing our more
encumbered phosphine/N-heterocyclic carbene (NHC) catalyst,
3,[2i,9] led to a dramatic switch in labeling selectivity in favor of
near-exclusive aryl labeling. Thus, these observations are in line
with our original hypothesis regarding increasing the bulk of the
ligand pair (Scheme 1, Path A).[10]
Catalyst design for site-selective C-H activation is
a
prominent and important area of on-going research in organic
synthesis.[1] To this end, deuterium labeling provides an
insightful means of probing catalyst activity and C-H bond
selectivity, either for isotope incorporation itself, or to underpin
further synthetic transformations.[2] In this regard, based on the
versatility of isotopically-labeled aldehydes as building blocks for
use in mechanistic and pharmaceutical science, a small number
of studies have reported hydrogen isotope exchange (HIE) on
the formyl moiety, albeit accompanied by aryl labelling (Scheme
1, top).[3] Despite the distinct nature of the aromatic and
aldehyde positions, little effort appears to have been made to
develop a formyl-selective HIE direct from the unlabeled
aldehyde.[4] Herein, we report our preliminary investigations to
establish such a formyl-selective labeling of aryl aldehydes.
Our previous studies on the iridium-catalyzed deuterium-
labeling of aromatic carbonyl derivatives[2i] have showed that a
Scheme 2. Hypothesis testing for aryl-selective labeling of aldehydes.
Following our proposed catalyst design for a formyl-selective
aldehyde labeling, we discovered that the large/small ligand
combination in NHC/chloro catalyst 4a,[11] bearing an overall
smaller ancillary ligand sphere than 2 or 3, delivered appreciably
encouragingly levels of formyl labeling selectivity (Scheme 3).
Although other NHC/Cl catalysts displayed similar activity,[10]
only catalyst 4b maximized formyl labeling whilst completely
suppressing formation of decarbonylated by-product 5. It should
Scheme 1. Ir-catalyzed labeling of aldehydes and mechanistic hypothesis.
Prof Dr W. J. Kerr, Dr M. Reid and Dr T. Tuttle
Department of Pure and Applied Chemistry, WestCHEM
University of Strathclyde, 295 Cathedral Street
Glasgow, Scotland, G1 1XL (U.K).
E-mail: w.kerr@strath.ac.uk; t.tuttle@strath.ac.uk
Supporting information for this article is given via a link at the end of
the document.
Scheme 3. Catalyst discovery for formyl-selective aldehyde labeling.
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Table 1. Substrate scope for formyl-selective aldehyde labeling.
Formyl
%D
Aryl
%D
Scheme 4. Improved synthetic route to labeled aldehyde 6p-d1.
Entry
Aldehyde
R
Yield, %
1
2
6a
6b
6c
6d
6e
6f
H
4-OBn
93
97
93
94
95
97
97
97
98
98
96
99
75
78
96
24
-
19
8
-
90
88
95
97
95
96
73
63
80
80
70
95
80
63
96
85
In a further demonstration of the utility of this catalytic formyl
labeling method, we have shown that silyl-protected phenol 6p,
employed in the synthesis of enantiopure d1-benzyl alcohols,[4d]
could be successfully labeled in a single, high-yielding step and
with a high level of deuterium incorporation (Scheme 4). This
method is superior to the existing route[4d] to the same product,
which employed stoichiometric quantities of reagents and
required five steps starting from alternative aldehyde, 6b.
3
4-OH
4
4-Ph
5
4-CF3
-
6
4-Cl
-
In a further extension of this work, we demonstrated that the
potentially air-sensitive d1-aldehydes need not be isolated, but
can instead be further elaborated in one pot, for example, via
7
6g
6h
6i
4-Br
-
8
4-F
8
12
-
Horner-Wadsworth-Emmons
olefination[12]
(Scheme
5).
Importantly, the resulting -deuterated, ,-unsaturated esters
8a-c have not been accessed by direct labeling of the
corresponding cinnamate esters.[13] Most notably, this procedure
also allowed the method to be extended to the labeling of
aliphatic aldehydes, such as in derivative 8c, with only minor
levels of deuterium incorporation at the enolisable site.
9
4-Me
10
11
12
13[a]
14[a]
15
16
6j
4-NO2
6k
6l
3-Br
-
3-NO2
-
6m
6n
1
3-CF3
-
3,5-di-Me
2-naphthaldehyde
1-naphthaldehyde
-
-
6o
-
[a] Reaction performed using 2.0 mol% 4b.
Scheme 5. One pot formyl labeling and olefination of aldehydes.
also be noted that, in agreement with our initial hypothesis, the
use of complexes with even more sterically demanding NHC
ligands decreased the formyl selectivity and, indeed, overall
catalyst reactivity.[10]
With an applicable and robust formyl labeling method in
hand, our attention turned to preliminary mechanistic
investigations into the hypotheses underpinning catalyst design.
Firstly, we established that the presence of the chloride ligand in
the optimal catalyst 4b was crucial, as replacement with the
more labile acetonitrile ligand in complex 9 resulted in low levels
of D-incorporation and equal amounts of aryl vs formyl C-H
activation (Scheme 6); additionally, introduction of a series of
silver salts in combination with complex 4b led to complete
arrest of the catalytic formyl labeling.[10] Secondly, 4-
(benzyloxy)benzyl alcohol was subjected to the optimized
conditions (but with H2 instead of D2), in order to detect any
aldehyde formation.[10] In this case, <2% conversion to the
corresponding aldehyde was observed, suggesting that a
Further investigation of the reaction conditions allowed
optimal catalyst 4b to be employed at loadings of 1–2 mol% by
extending the reaction time from 1 h to 3 h.[10] Under these
optimized conditions, a range of aromatic aldehydes were
selectively deuterated. As depicted in Table 1, unsubstituted and
para-substituted benzaldehydes (6a, and 6b–6j) were labeled
with good to excellent regioselectivity and isolated yields, with a
low level of aryl labeling detectable in only a few examples. A
series of meta-substituted substrates (6k–6n) were also well-
tolerated, while more encumbered aldehydes, such as 1-
naphthaldehyde 6o, remain challenging. Under the employed
conditions, the decarbonylation product 7 was not observed with
any of the substrates.
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ancillary ligand geometry in 14 allows axial coordination of the
aldehyde and subsequent formyl C-H activation to give Ir(V)
complex 15. From this intermediate, our DFT studies strongly
support reductive elimination of two of the three hydrides to give
dihydrogen complex 16, which can return to Ir(V) via oxidative
re-addition of the bound hydrogen to give 17, with a further
deuteride now cis to the acyl ligand.[15] Reductive elimination
from intermediate 17 then gives the labeled, bound aldehyde in
complex 18, in a microscopic reverse of the initial activation step
(14→15). Finally, the productive, formyl labeling cycle may
partition at Ir(III) intermediate 16, with decarbonylation of the
acyl ligand via migratory insertion (16→19). Reductive
elimination of the decarbonylation by-product from 19 leads to
carbonyl complex 20.
Scheme 6. Investigating the effect of the chloride ligand.
Following extensive binding conformer comparisons,[15] the
lowest potential energy surfaces (PESs) for aryl, formyl, and
decarbonylative labeling are summarized in Scheme 9.
Consistent with experiment, formyl labeling represents the
lowest energy pathway. The formyl C-H activation (14→15) is
predicted to be enthalpically flat on the PES, with the
Ir(V)→Ir(III) reductive elimination (15→16) being turnover-
limiting. From transition state calculations, the formyl activation
hydrogen borrowing mechanism[14] plays only a minor role.
Further to these initial experimental studies, density
functional theory (DFT) has been utilized to model proposed
labeling mechanisms consistent with both the initial hypothesis
and all available experimental evidence.[15] To begin, the free
energy differences in the DCM-solvated cis- and trans-isomers
of the deuterium-activated catalysts derived from pre-catalysts 2,
3, and 4b were assessed (Scheme 7). In the progression
towards more formyl-selective labeling catalysts (3→2→4b), the
trans/cis energy gap diminishes. Moreover, the energetic order
of the cis- and trans-isomers was shown to be reversed on
moving to the optimized catalyst, 4b, with its ΔGcis/trans being the
smallest of the three catalysts studied.
Scheme 7. Computational support for cis/trans ligand model.
Following this initial modelling study, the mechanistic details
of the competing labeling processes were investigated for
substrate 6a with catalyst 4b. Overall, three competing pathways
are proposed, which account for the three observed products:
aryl labeling, formyl labeling, and decarbonylation (Scheme 8).
The aryl labeling pathway is calculated to proceed via an all-
Ir(III) cycle with trans ancillary ligands (10–13), as elucidated in
our earlier reports.[2i,11] In contrast, and in comparison with the
labeling of sulfonamides using iridium NHC/chloro complexes of
type 4,[11] a distinct mechanism for aldehyde C-H activation with
these catalysts is revealed by the computed formyl labeling
pathway. More specifically, after catalyst activation, the cis
Scheme 8. DFT mechanisms for aryl, formyl, and decarbonylative labeling.
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Scheme 9. Calculated PESs for formyl vs. aryl vs. decarbonylative labeling. [15]
step is seen to be coupled with a rotation of one iso-propyl group
on the ligand to accommodate the substrate (TS 14-15 in
Scheme 9)[15] Conversely, the barrier to the classical ortho-
labeling process (TS 10-11) is unproductively high relative to
formyl labeling.[16] Finally, the partition towards decarbonylation
(TS 16-19) represents the most energetically unfavorable of all
these processes at the catalytically-relevant temperature
(298.15 K); this is in qualitative agreement with only trace
observation of such by-products.
Keywords: C-H activation • aldehyde • deuterium • iridium • DFT
[1]
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Hashiguchi, S. M. Bischof, M. M. Konnick, R. A. Periana, Acc. Chem.
Res. 2012, 45, 885-898.
In summary, we have developed a mild and highly selective
catalytic process for the formyl C-H labeling of a range of
functionalized aryl aldehydes. This direct method is an
improvement on existing stepwise routes towards preparatively
important and pharmaceutically-valuable d1-aldehydes, and can
also be employed in a one-pot process leading to derivatization
of the labeled formyl moiety. DFT analysis supports competition
between an Ir(III) catalytic cycle for aryl labelling, and previously
unreported Ir(III)/Ir(V) cycles for formyl labeling and partitioning
decarbonylation. Based on these initial investigations, further
studies on the site-selective C-H activation of aldehydes are
currently underway in our laboratory and will be reported in due
course.
[2]
For selected examples of metal-catalyzed labeling, see: a) S. Ma, G.
Villa, P. S. Thuy-Boun, A. Homs, J.-Q. Yu, Angew. Chem. Int. Ed. 2014,
53, 734-737; Angew. Chem. 2014, 126, 753-756; b) M. H. Emmert, J. B.
Gary, J. M. Villalobos, M. S. Sanford, Angew. Chem. Int. Ed. 2010, 49,
5884-5886; Angew. Chem. 2010, 122, 6020-6022; c) A. Di Giuseppe, R.
Castarlenas, J. J. Pérez-Torrente, F. J. Lahoz, V. Polo, L. A. Oro,
Angew. Chem. Int. Ed. 2011, 50, 3938-3942; Angew. Chem. 2011, 123,
4024-4028; d) J. Campos, A. C. Esqueda, J. López-Serrano, L.
Sánchez, F. P. Cossio, A. de Cozar, E. Álvarez, C. Maya, E. Carmona,
J. Am. Chem. Soc. 2010, 132, 16765-16767; e) L. Neubert, D. Michalik,
S. Bähn, S. Imm, H. Neumann, J. Atzrodt, V. Derdau, W. Holla, M.
Beller, J. Am. Chem. Soc. 2012, 134, 12239-12244; f) A. Prades, M.
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Angew. Chem. 2007, 119, 2319-2322; h) M. Parmentier, T. Hartung, A.
Pfaltz, D. Muri, Chem. Eur. J. 2014, 20, 11496-11504; i) J. A. Brown, A.
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Acknowledgements
W.J.K. and M.R. would like to thank the Carnegie Trust for
funding, and the EPSRC UK National Mass Spectrometry
Facility at Swansea University for analyses.
[3]
a) M. R. Chappelle, A. D. Morgan, N. C. O. Tomkinson, T. M. Willson,
in Synth. Appl. Isotop. Lab. Comp. Proceedings of the 7th International
Symposium (Eds.: U. Pleiss, R. Voges), Wiley, New York, 2001, pp.
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80–83; b) M. R. Chappelle, C. R. Hawes, J. Labelled Compd.
Radiopharm. 2010, 53, 745-751; c) M. B. Skaddan, C. M. Yung, R. G.
Bergman, Org. Lett. 2004, 6, 11-13.
[4]
[5]
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Tetrahedron Lett. 2004, 45, 2787-2789; b) S. B. Boga, A. B. Alhassan,
D. Hesk, Tetrahedron Lett. 2014, 55, 4442-4444; c) S. Korsager, R. H.
Taaning, A. T. Lindhardt, T. Skrydstrup, J. Org. Chem. 2013, 78, 6112-
6120; d) D. W. Barnett, M. S. Refaei, R. W. Curley Jr., J. Labelled
Compd. Radiopharm. 2013, 56, 6-11.
Previous studies in the Rh- and Ir-catalyzed decarbonylation of
aldehydes have enforced this substrate binding mode via bidentate
ligand design. See, for example: a) E. P. K. Olsen, T. Singh, P. Harris,
P. G. Andersson, R. Madsen, J. Am. Chem. Soc. 2015, 137, 834-842;
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[6]
[7]
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2013, 19, 3125-3130.
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see: a) G. N. Nilsson, W. J. Kerr, J. Labelled Compd. Radiopharm.
2010, 53, 662-667; b) R. Salter, J. Labelled Compd. Radiopharm. 2010,
53, 645-657; c) J. Atzrodt, V. Derdau, T. Fey, J. Zimmermann, Angew.
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[8]
[9]
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a) A. R. Cochrane, S. Irvine, W. J. Kerr, M. Reid, S. Andersson, G.
Nilsson, J. Labelled Compd. Radiopharm. 2013, 56, 451-454; b) A. R.
Cochrane, C. Idziak, W. J. Kerr, B. Mondal, L. C. Paterson, T. Tuttle, S.
Andersson, G. N. Nilsson, Org. Biomol. Chem. 2014, 12, 3598-3603; c)
A. R. Kennedy, W. J. Kerr, R. Moir, M. Reid, Org. Biomol. Chem. 2014,
12, 7927-7931; d) J. Atzrodt, V. Derdau, W. J. Kerr, M. Reid, P. Rojahn,
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[10] For further details, see the electronic supporting information (ESI).
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[12] B. E. Maryanoff, A. B. Reitz, Chem. Rev. 1989, 89, 863-927.
[13] For selected examples of labeling α,β-unsaturated substrates directly,
see: a) W. J. Kerr, R. J. Mudd, L. C. Paterson, J. A. Brown, Chem. Eur.
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[15] Details of all calculation methods, along with additional calculations not
presented in the manuscript, can be found in the ESI.
[16] The barrier to aryl C-H insertion is 7.4 kcal/mol lower in energy when
using catalyst 3, for which formyl labeling is also disfavoured,
consistent with the observed ortho-selectivity with 3 (Scheme 2); see
the ESI.
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Entry for the Table of Contents
COMMUNICATION
Al(D)hydes. An iridium catalyst
system has been designed to effect
formyl over aryl C-H activation of
aromatic aldehydes. Computational
studies support kinetic product control
over competing aromatic labeling and
decarbonylation pathways.
Prof. Dr W. J. Kerr,* Dr M. Reid, and Dr
T. Tuttle*
Page No. – Page No.
Iridium-catalyzed Formyl-selective
Deuteration of Aldehydes
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