Metal-catalysed azidation of tertiary C-H bonds suitable for late-stage functionalization

Article abstract of DOI:10.1038/nature14127

Many enzymes oxidize unactivated aliphatic C-H bonds selectively to form alcohols; however, biological systems do not possess enzymes that catalyse the analogous aminations of C-H bonds. The absence of such enzymes limits the discovery of potential medicinal candidates because nitrogen-containing groups are crucial to the biological activity of therapeutic agents and clinically useful natural products. In one prominent example illustrating the importance of incorporating nitrogen-based functionality, the conversion of the ketone of erythromycin to the -N(Me)CH₂ - group in azithromycin leads to a compound that can be dosed once daily with a shorter treatment time. For such reasons, synthetic chemists have sought catalysts that directly convert C-H bonds to C-N bonds. Most currently used catalysts for C-H bond amination are ill suited to the intermolecular functionalization of complex molecules because they require excess substrate or directing groups, harsh reaction conditions, weak or acidic C-H bonds, or reagents containing specialized groups on the nitrogen atom. Among C-H bond amination reactions, those forming a C-N bond at a tertiary alkyl group would be particularly valuable, because this linkage is difficult to form from ketones or alcohols that might be created in a biosynthetic pathway by oxidation. Here we report a mild, selective, iron-catalysed azidation of tertiary C-H bonds that occurs without excess of the valuable substrate. The reaction tolerates aqueous environments and is suitable for the functionalization of complex structures in the late stages of a multistep synthesis. Moreover, this azidation makes it possible to install a range of nitrogen-based functional groups, including those from Huisgen 'click' cycloadditions and the Staudinger ligation. We anticipate that these reactions will create opportunities to modify natural products, their precursors and their derivatives to produce analogues that contain different polarity and charge as a result of nitrogen-containing groups. It could also be used to help identify targets of biologically active molecules by creating a point of attachment - for example, to fluorescent tags or 'handles' for affinity chromatography - directly on complex molecular structures.

Full text of DOI:10.1038/nature14127

LETTER
doi:10.1038/nature14127
Metal-catalysed azidation of tertiary C–H bonds
suitable for late-stage functionalization
Ankit Sharma1 & John F. Hartwig1
Many enzymes oxidize unactivated aliphatic C–H bonds selectively to products, their precursors and their derivatives to produce analo-
form alcohols; however, biological systems do not possess enzymes gues that contain different polarity and charge as a result of nitro-
that catalyse the analogous aminations of C–H bonds1,2. The absence gen-containing groups. It could also be used to help identify targets
of such enzymes limits the discovery of potential medicinal candi- of biologically active molecules by creating a point of attachment—
datesbecausenitrogen-containinggroupsarecrucialtothebiological for example, to fluorescent tags or ‘handles’ for affinity chromato-
activity of therapeutic agents and clinically useful natural products. graphy—directly on complex molecular structures.
In one prominent example illustrating the importance of incorp-
orating nitrogen-based functionality, the conversion of the ketone
of erythromycin to the –N(Me)CH2– group in azithromycin leads
To develop a mild method for the conversion of an alkyl C–H bond
to an alkyl C–N bond, we focused on reactions of the hypervalent iodine
reagent 1 containing an azide unit (Fig. 1). Such a reagent is related to
toacompoundthatcan bedosed oncedailywitha shorter treatment hypervalent reagents commonly used for oxidation20
and is thermally
stable (up to 130uC)21. It has sufficient thermodynamic potential to
convert alkyl C–H bonds to alkyl azides, but the published reactions
have been limited to simple hydrocarbons, typically used in excess
amounts, or activatedC–H bonds athigh temperatures in the presence
ofradical initiators21. Thus, the current azidationsofC–Hbonds bythis
reagent21 are not suitable for late-stage functionalization of complex mole-
cules. If an appropriate transition-metal catalyst for C–H bond func-
tionalization with this hypervalent iodine reagent could be identified,
then C–H bond amination reactions that incorporate an azide into
complex molecules with site selectivity could be devised. Previously,
iron– and manganese–porphyrin complexes were reported to catalyse
the formation of alkyl azides using sodium azide and iodosobenzene or
tBuOOH as oxidants, but thereactions were limited tohydrocarbons, an
excess of the alkane (10 equiv.) was required, and a major by-product
time3,4. For such reasons, synthetic chemists have sought catalysts
that directly convert C–H bonds to C–N bonds. Most currently used
catalysts for C–Hbondaminationareillsuited totheintermolecular
functionalization of complex molecules because they require excess
substrate or directing groups, harsh reaction conditions, weak or
acidic C–H bonds, or reagents containing specialized groups on the
nitrogen atom5–14. Among C–Hbond amination reactions, thoseform-
ing a C–N bond at a tertiary alkyl group would be particularly valu-
able,becausethislinkageisdifficulttoformfromketonesoralcohols
that might be created in a biosynthetic pathway by oxidation15. Here
we report a mild, selective, iron-catalysed azidation of tertiary C–H
bonds that occurs without excess of the valuable substrate. The reac-
tion tolerates aqueous environments and is suitable for the functio-
nalization of complex structures in the late stages of a multistep
synthesis. Moreover, this azidation makes itpossibleto install arange
of nitrogen-based functional groups, including those from Huisgen
‘click’ cycloadditions and the Staudinger ligation16–19. We anticip-
ate that these reactions will create opportunities to modify natural
was the corresponding alcohol22–24
.
To identify a metal complex that would catalyse the azidation of C–H
bonds with 1 under mild conditions, we investigated the reaction of
cis-decalin. Various metal complexes, including metal porphyrins, were
Bz pNO2
O
N3
I
H
Fe(OAc)2*
N3
HN
L1–L11
O
1. Pd/C, H2
H
+
CH3CN
(0.5 ml)
23 °C
2. pNO2BzCl
Major diasteromer
H
3a†
1.0 equiv.
tBu
1, 2.0 equiv.
4a, 80%‡
Py
N
tBu
O
N
N
N
N
Py
N
Py
Py
N
N
Py
N
N
Py
Py
L1, 4%
Py = pyridine
L2, 7%, 3.2:1
L3, 10%, 3.0:1
L4,11%, 4.3:1
L5, 3%, 2.3:1
L6, 5%, 3.6:1
CN
O
O
O
O
N
O
O
O
O
N
O
N
O
N
N
N
N
N
N
N
N
N
tBu
tBu
Ph
Ph
iPr
iPr
Ph
Ph
L10, 35%, 4.1:1
L7, 10%, 2.8:1
L8, 20%, 4.0:1
L9, 22%, 4.0:1
L11, 75%, 4.3:1
Figure 1
|
Development of a catalyst for the azidation of aliphatic C–H
{Combined yield of isomers. Middle and bottom rows, structural formulae of
ligands L1–L11. Also shown are yields and the ratios of isomers determined by
bonds. Top row, reactions studied. *Conditions: 10.0 mol% Fe(OAc)2, 11.0
mol% ligand (L1–L11), cis-decalin (0.2 mmol, 1.0 equiv.) and 1 (0.4 mmol, 2.0 gas chromatography analysis with dodecane as internal standard; ratios are not
equiv.), 23uC, 1 ml of CH3CN. {The relative configuration of the major
diastereomer of 3a was confirmed by X-ray crystallographic analysis of 4a.
corrected for response factors of minor isomers.
1Department of Chemistry, University of California, Berkeley, California 94720, USA.
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LETTER RESEARCH
tested as catalysts with the hydrocarbon as limiting reagent; only iron with the catalyst containing ligand L11 proceeded in good yield and
complexes provided measurable yields of azide product at 23uC (Sup- higher trans:cis selectivity (65%, 6.3:1; Supplementary Table 2).
plementary Table 1). Combinations of Fe(OAc)2 and various bi-, tri- Reactions in acetonitrile were faster, but occurred with lower select-
and tetra-dentate nitrogen ligands (L1–L5 in Fig. 1), including those ivity. Reactions in a mixture of EtOAc and water (5:1) occurred simi-
that catalyse the selective hydroxylation of aliphatic C–H bonds (L1 larly to those in pure EtOAc (63%, 6:1).
and L3)25,26, provided low yields of the product 3a (Fig. 1; 3–11%).
The azidation of the C–H bond of a series of hydrocarbons occurred
However, substantial yields of 3a were observed with iron complexes
of oxazoline-derived ligands, particularly with those possessing larger
N–Fe–N ‘bite’ angles (L6–L9 in Fig. 1). Finally, we found that reac-
tions of iron complexes containing tridentate nitrogen ligands of the
pyboxfamily(L10andL11in Fig. 1) providedproduct3ain goodyield
with high selectivity for reaction at a tertiary C–H bond (75%, 4.3:1
ratio of diastereomers). Reactions conducted in ethyl acetate (EtOAc)
in excellent yields with high selectivity for a tertiary C–H bond over the
secondary and primary C–H bonds (Supplementary Table 3), setting the
stage for azidation of the tertiary C–H bonds in molecules containing
a series of functional groups. The azidation reaction with derivatives of
dihydrocitronellol containing two electronically distinct tertiary C–H
bonds and many secondary C–H bonds is shown in Fig. 2a. These reac-
tions revealed the inherent electronic selectivity of the azidation reaction
Remote
Remote
Proximal
Proximal
O
N3
I
Fe(OAc)2*
L11
O
O
O
N3
H
H
H
N
FG
FG
+
N
N
CH3CN
50 °C
L11
iPr
iPr
1, 2.0 equiv.
a
Evaluation of site-selectivity for C-H bond azidation
N3
Me
H
N3
H
N3
H
N3
H
N3
H
CN
Br
OAc
OAc
3s, 67%†, 12:1
3k, 50%,10:1
3l, 45%,5:1
3m, 45%,8:1
3n, 43%,8:1
O
N3
H
N3
H
N3
H
H
N3
Me
CONH2
CO2H
CO2Me
N3
3t, 70%†, 14:1
3o, 56%,12:1
3r, 53%, 5:1
3p, 65%
3q, 51%,10:1
b
C-H bond azidation complex molecular scaffolds containing multiple tertiary centres
O
O
O
N3
O
NCO2Et
N3
N3
N3
H
H
H
3v, 52%,10:1:1
15%, 3:1:1‡
3b, 80%
10%, 1:1‡
O
3u, 50%,11:1:1
20%, 2:1:1‡
3w, 53%,10:1:1
10%, 3:1‡
O
H
OAc
H
TBSO
OMe
H
H
H
N3
H
TBSO
N3
N3
3y, 75%, 6:1†§
7%, 2:1‡
3z, 24%, 5:1†§
5%,1:1‡
3x, 35%, 8:2:1
25%, 2:1:1‡
c
Late-stage C-H bond azidation tetrahydrogibberellic acid derivative
H
H
H
H
OH
O
Fe(OAc)2*
L11
O
OH
N3
I
O
O
O
O
O
8
O
+
CH3CN
50 °C
H
H
N3
H
OH
O
OH
O
6
6, 75%
15%‡
5, 6:1
2.0 equiv.
Figure 2
|
Evaluation of the effect of the steric and electronic environment used as solvent. b, C–H bond azidation of complex molecular scaffolds
on site selectivity for the azidation of aliphatic tertiary C–H bonds. Top row, containing multiple tertiary centres. Yields of products 3u–3z were also
reaction studied. *Conditions: 10.0 mol% Fe(OAc)2, 11.0 mol% ligand compared to those of the benzoyl-peroxide-initiated reaction, as follows.
L11, substrate (on left: 0.2 mmol, 1.0 equiv.) and 1 (0.6 mmol, 3.0 equiv.), 23uC, {Conditions: 10.0 mol% BzOOBz, substrate (0.2 mmol, 1.0 equiv.) and 1
1 ml of CH3CN. Isolated yields of major azide products are reported unless
mentioned otherwise. The ratios of isomers were determined by gas
chromatography analysis with dodecane as internal standard, and are not
(0.6 mmol, 3.0 equiv.), 84uC and 1,2-dichloroethane (1.0 ml) as solvent. The
yield and ratios of isomers were determined by gas chromatography analysis
with dodecane as internal standard. The ratios refer to the major product versus
corrected for response factors of minor isomers. a, Evaluation of site selectivity minor product determined to be isomers by mass spectrometry. c, Late-stage
for C–H bond azidation. The ratios reported reflect the site selectivity for
C–H bond azidation of a tetrahydrogibberellic acid derivative. As reaction at
reaction at the two tertiary C–H bonds (3k to 3r) or the two benzylic C–H
top, except substrate is 5, and 6 is product. 1Diastereoselectivity was measured
bonds (3s,3t). 3k–3t are the products formed from the azidation. {EtOAc was by 1H NMR of crude reaction mixture.
|
|
Unidentifiable mixture of products.
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RESEARCH LETTER
and its functional-group compatibility. The C–H bond azidation was carbon bound to the azide is independent of the configuration in the
selective for reaction at the more electron-rich, remote, tertiary C–H reactant. However, this stereochemical outcome of our reactions allows
bond, resulting in good isolated yields of the pure major isomers formed one to use mixtures of diastereomeric reactants (see Supplementary
by the reaction (3k–3q in Fig. 2a). The regioselectivity of azidation at the Table 3 and Fig. 2; explicitly, 2b to form 3b and 5 to form 6) to provide
two electronically distinct tertiary C–H bonds was influenced by the one major diastereomer of the azide product (see below).
distance of the electron-withdrawing group from the proximal tertiary
C–H bond (3k and 3l). In these cases, the regioselectivity of the C–H
bond azidation reaction mirrors the regioselectivity of a wide range of
oxidation reactions27. Functional groups—such as an alcohol protected
as an acetoxy group (3k and 3l), a bromide (3m), a nitrile (3m), an ester
(3o), a carboxylic acid (3p) and an amide (3q)—were tolerated. Func-
tional groups like a carboxylic acid (3p) and an amide (3q) that could act
as directing groups influenced the selectivity by their electronic prop-
erties, rather than by coordination to the catalyst. This higher reactivity
of more electron-rich C–H bonds was also observed for cyclic structures.
4-iso-Propylcyclohexanone underwent azidation with high regioselec-
tivity for the more electron-rich of the two tertiary C–H bonds (3r in
Fig. 2a). Investigation of the reactions of substituted arenes showed that
tertiaryand secondary benzylic C–H bonds were functionalized selectively
in the presence of primary benzylic C–H bonds (3s and 3t in Fig. 2a).
Having revealed high regioselectivity for C–H bond azidation, we
assessed the potential of this reaction for azidation of the C–H bonds in
more complex scaffolds containing several functional groups and strained
rings that could react instead of a C–H bond or influence the identity of
the C–H bond that undergoes azidation (Fig. 2b). Cyclic ketones pre-
pared from (2)-carvone underwent azidation at the tertiary C–H bond
remotefromthe ketonewithhighregioselectivity. These reactions occurred
in the presence of epoxides, aziridines and cyclopropanes in good iso-
lated yields (3u–3w in Fig. 2b). Minor azidation products were also
observed by gas chromatography–mass spectrometry. These products
were formed in amounts too small for isolation and were not character-
ized. A mixture of diastereomers of a-dihydropinene (2b, 5:1) contain-
ing three electronicallysimilar, but sterically distinct, tertiary C–H bonds
reacted to give 80% isolated yield of a single isomer of azide 3b at room
temperature. The strained four-membered ring was tolerated, suggesting
a fast recombination of the likely radical intermediates. Acetoxymenthol
containing two electronically similar tertiary C–H bonds reacted pref-
erentiallyattheiso-propylsidechaintoprovideonemajorconstitutional
isomer in moderate isolated yield (3x in Fig. 2b). This selectivity, pre-
sumably, results from the greater conformational flexibility of the iso-
propyl side chain. Isomeric products from azidation of a different C–H
bond were observed as minor products; again, these products were
formed in quantities too low for full characterization, but were shown
to be isomers by mass spectrometry.
Biologicallyactivemoleculescontaining multiplebenzylic and tertiary
C–H bonds also reacted selectively. Podocarpic acid and its derivatives
have been reported to exhibit a wide variety of biological activities,
including antileukaemic activity, inhibition of plant cell growth, and
anti-inflammatory properties. A podocarpic acid derivative underwent
selective azidation at the benzylic C–H bond in high yields and good
diastereoselectivity (3y in Fig. 2b). Similar selectivity was also observed
for the azidation of an oestrone (3z in Fig. 2b).
The reaction of a gibberellic acid derivative illustrates the ability to
conduct the azidation of complex structures (Fig. 2c). Gibberellic acid
is a plant hormone that regulates growth and influences developmental
processes, including cell elongation and germination. The gibberellic acid
derivative5isa pentacyclic diterpenecontaining four tertiary C–Hbonds.
Based on the data just presented, the most electron-rich and sterically
least hindered tertiary C–H bond, the one at carbon 8, should react
selectively. In addition, the stereochemical outcome of the azidation of
cis- and trans-decalin and a-dihydropinene (Supplementary Table 3 and
Fig. 2b) suggested that the configuration of the reactive centre in sub-
strate 5 would have a negligible influence on the diastereomeric ratio
of product 6 (Fig. 2c). Indeed, the azidation of a mixture of diaster-
eomers of 5provided the corresponding azide6 asasingle isolateddia-
stereoisomer in 75% yield (Fig. 2c) from exo-attack of the azide unit at
C(8).
Finally, we also tested functionalizations of the complex scaffolds
shown in Fig. 2b and c by reactions initiated with benzoyl peroxide. In
all cases, poor yields and selectivities were observed from the reactions
initiated by the peroxide. The yields of the products from reaction of
the substrates in Fig. 2b were low in all cases and formed mixtures of
isomeric products with poor selectivity. In addition, gibberellic acid deri-
vative 5 decomposed to form a complex mixture of products in the
presence of azide 1 and the peroxide. This distinct reaction course in
the presence and absence of the iron catalyst suggests that the C–N bond
is formed by two different processes in thetwosystems, and underscores
the importance of the iron catalyst to create a reaction that is suitable for
late-stage functionalization of complex molecules.
Although detailed mechanistic studies have not yet been conducted,
several observations reveal the general features of the mechanism. The
siteselectivitiesandstereochemicaloutcomeoftheazidationofcis-and
trans-decalin and a-dihydropinene strongly suggest that a tertiary alkyl
radical is generated (Supplementary Table 3 and Fig. 2b). Attempts to
use radical clocks to assess more directly a potential alkyl radical were
Unlike the stereoretentive property of the metal-catalysed insertions
of nitrenes or carbenes into C–H bonds8,9,28, the configuration of the
Table 1
|
Experiments to evaluate the involvement of radical intermediates and the role of the iron catalyst
O
N3
I
tBu
OH
tBu
N3
Cat.
OH
N
O
N
N
(10 mol%)
+
CH3CN
(0.5 ml)
Additive
CN
CN
cis or trans
1, 2.0 equiv.
3a
TEMPO
BHT
ABCN
1.0 equiv.
Entry
Substrate
Catalyst
Temperature
(uC)
Additive
Yield
(%)
Selectivity
1
2
3{
4{
5{
6{
cis
cis
cis
trans
cis
Fe(OAc)2/L11
Fe(OAc)2/L11
Fe(OAc)2/L11
Fe(OAc)2/L11
BzOOBz
23
23
80
80
80
80
TEMPO*
BHT*
NA
NA
ABCN{
ABCN{
3
3
55
43
40
33
NA
NA
3.2
3.2
1.7
1.7
trans
BzOOBz
Conditions: 10.0 mol% catalyst, cis- or trans-decalin (0.2 mmol, 1.0 equiv.) and 1 (0.4 mmol, 2.0 equiv.), 2 h. The yield and ratios of isomers were determined by gas chromatography analysis with dodecane as
internal standard and not corrected for response factors of minor isomers. NA, not applicable.
* 1.0 equiv. was added.
{ EtOAc was used as solvent.
{ 1.0 mol% was added.
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LETTER RESEARCH
R
R
H
NHCOR
Boc
N
Heterocyles by sequential
C-H bond amination
Amides
a
c
f
n
4a, 80%
11a,b
(n=1,2)
N3
b
e
c
N
O
OEt
N
Tetrazole
synthesis
N
Ph
O
N
N
12
9, 72%
Heteroarenes
d
H
O
HO
H
O
O
TBSO
O
OMe
Attachment of
fluorescent tag
OH
H
N
N
8, 70%
O
OH
N
N
O
N
Bifunctional
biomolecules
O
3
7, 80%
H
H
N
Amines
TBSO
O
S
NH3Cl
O
H
10, 70%
4
NH
H
HN
O
Figure 3
|
Introduction of a series of nitrogen-containing functionalities via NaBH4 (3 equiv.), MeOH; e, (1) TfOH (1.0 equiv.), toluene (2.0 equiv.),
C–H bond azidation. a, Azide (1.0 equiv.), Fe cat., Fmoc-OSuc (1.5 equiv.),
65uC, benzene, 24 h (see ref. 19 for details). b, BzCN (2 equiv.), 130uC, 48 h;
c, CuSO4 (10 mol%), alkyne (2 equiv.), DMF, 48 h; d, CuSO4 (10 mol%),
ethyl 3-ethoxyacrylate; (2) 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ), EtOAc, 5 min (ref. 18); f, (1) Pd/C, H2, MeOH; (2) Ac2O,
dichloromethane, 12 h.
hampered by the poor reactivity of the appropriate substrates (see Sup- with azido gibberellic acid derivative 6, and an alkyne attached to
plementary Information for more details), but the proposed radical biotin coupled with azido podocarpic acid derivative 3y. These reactions
intermediate is consistent with the selectivity for azidation of the more illustrate how azidation and cycloaddition can create bioconjugation
electron-rich, less polarized, and thus weaker, tertiary C–H bonds methods for visualization and identification of cellular targets of biologic-
(Fig. 2)27. Furthermore,additionof1equiv. ofBHTandTEMPO(struc- ally active natural products30.
tures shown in Table 1), which are known to quench radicals, resulted
in complete inhibition of theazidation reaction (Table 1, entries 1 and2).
Finally, the kinetic isotope effect (KIE) for azidation of ethylbenzene
and ethylbenzene-d10 in separate vessels from initialreaction rates was
observed to be 5.0 6 0.3, implying that the cleavage of the C–H bond is
the overall turnover-limiting step.
Much development of this C–H bond functionalization method re-
mains to be accomplished, but a wide range of applications and exten-
sions of the azidation reaction can be envisioned. The modularity of the
catalyst creates further opportunities for site selectivity, and the stereo-
chemical content of the ligand creates the potential for enantioselective
azidation. The cycloadditions of azides could make possible conjugation
to antibodies, and the simple reduction of the azide and the tolerance
of the reaction to water creates the potential to intercept biosynthetic
sequences and install an amino group in place of a hydroxyl group in the
finalstages. Finally, we anticipate that this process willspur development
of new classes of catalysts for the azidation of C–H bonds that could
proceed by distinct mechanisms with distinct selectivities for primary,
secondary and tertiary C–H bonds. As rhodium-catalysed amination
reactions develop further, the two classes of systems for C–H bond
amination should begin to provide a set of tools for incorporation of
nitrogen atoms that parallels the existing set of tools for the chemical
and enzymatic oxidation of C–H bonds.
To assess the role of the iron catalyst in this transformation, we com-
pared the iron-catalysed azidations of the complex scaffolds in Fig. 2b
and c with the reactions initiated by benzoyl peroxide. As noted above,
poor yields were observed in all cases from the reactions initiated by the
peroxide. The selectivities for formation of the azidation product from
these reactions were lower than those of the iron-catalysed reactions.
In addition, the diastereomeric ratio of product 3a formed from dec-
alin and azide 1 in the presence of an organic radical initiator was dif-
ferent from that formed from the iron-catalysed reaction conducted at
the 80uC required for the peroxide-initiated process (Table 1, entries
3–6). These differences in selectivities are all consistent with a different
species forming the C–N bond during the iron-catalysed reaction and
during the radical-initiated process. One possible origin of this differ-
ence is formation of the C–N bond in the iron-catalysed process by
reaction of an alkyl radical with an iron azide intermediate.
Received 8 October; accepted 28 November 2014.
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useful functionalities attached to the original substrate by a C–N bond
(Fig. 3)16–19. The primary amine formed from azides 3a and 3z containing
a fully or partially substituted carbon atom (4a and 10), and heterocycles
such as tetrazole 9 from azide 3f, form in good yields (Supplementary
Table 3)29. The azides (for example, 3d and 3e, Supplementary Table 3)
also undergo intramolecular cyclization under conditions reported re-
cently19 to form various heterocycles, creatinga route to nitrogen hetero-
cycles, such as 11, from alkanes by two C–H bond amination reactions.
Finally, the azide functionality undergoes Huisgen cycloaddition reac-
tions. For example, an alkyne tethered to a fluorescent tag coupled
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RESEARCH LETTER
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Acknowledgements We thank the US NIH (4R37GM055382 to J.F.H.) and the Swiss
National Science Foundation (SNSF; PBGEP2_145544 to AS) for financial support. We
thank A. DiPasquale for assistance with crystallographic data and acknowledge US NIH
shared instrumentation grant S10-RR027172.
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Author Contributions A.S. conducted the experiments. A.S. and J.F.H. conceived and
designed the project, analysed the data and prepared this manuscript. X-ray crystal
structures are deposited in the Cambridge Crystallographic Data Centre (CCDC
1027821–1027822).
Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial interests.
Readers are welcome to comment on the online version of the paper. Correspondence
and requests for materials should be addressed to J.F.H. (jhartwig@berkeley.edu).
22. Hill, C. L., Smegal, J. A. & Henly, T. J. Catalytic replacement of unactivated alkane
carbon-hydrogen bonds with carbon-X bonds (X 5 nitrogen, oxygen, chlorine,
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