Practical and innate carbon-hydrogen functionalization of heterocycles

Article abstract of DOI:10.1038/nature11680

Nitrogen-rich heterocyclic compounds have had a profound effect on human health because these chemical motifs are found in a large number of drugs used to combat a broad range of diseases and pathophysiological conditions. Advances in transition-metal-med

Full text of DOI:10.1038/nature11680

LETTER
doi:10.1038/nature11680
Practical and innate carbon–hydrogen
functionalization of heterocycles
Yuta Fujiwara1*, Janice A. Dixon1*, Fionn O’Hara1*, Erik Daa Funder1, Darryl D. Dixon1, Rodrigo A. Rodriguez1, Ryan D. Baxter1,
1
Bart Herle , Neal Sach1,2, Michael R. Collins1,2, Yoshihiro Ishihara1 & Phil S. Baran1
´
Nitrogen-rich heterocyclic compounds have had a profound effect on products that cannot be efficiently generated by standard Minisci pro-
human health because these chemical motifs are found in a large tocols and would otherwise require programmed, multistep processes.
number of drugs used to combat a broad range of diseases and patho-
physiological conditions. Advances in transition-metal-mediated
cross-coupling have simplified the synthesis of such molecules; how-
ever, C–H functionalization of medicinally important heterocycles
that does not rely on pre-functionalized starting materials is an under-
developed area1–9. Unfortunately, the innate properties of heterocycles
that make them so desirable for biological applications—such as
aqueous solubility and their ability to act as ligands—render them
challenging substrates for direct chemical functionalization. Here
we report that zinc sulphinate salts can be used to transfer alkyl
radicals to heterocycles, allowing for the mild (moderate tempera-
ture, 50 6C or less), direct and operationally simple formation of
medicinally relevant C–C bonds while reacting in a complementary
fashion to other innate C–H functionalization methods2–6 (Minisci,
borono-Minisci, electrophilic aromatic substitution, transition-
metal-mediated C–H insertion and C–H deprotonation). We pre-
pared a toolkit of these reagents and studied their reactivity across a
wide range of heterocycles (natural products, drugs and building
blocks) without recourse to protecting-group chemistry. The
reagents can even be used in tandem fashion in a single pot in the
presence of water and air.
These salts represent examples of what we anticipate to be a general
X = halogen; R–[M]
a
Conventional cross-coupling
‘Programmed’
X = H; Alkyl–CO2H/Ar–B(OH)2
Het
X
Het
R
Minisci/borono-Minisci
‘Innate’
X = H; (R–SO2)2Zn
This work
‘Innate’
b
O
C
Minisci
• Acyl and alkyl radicals
(refs 2 and 3)
C–C
83 kcal mol–1
R
R
OH
OH
∼
OH
B
Borono-Minisci
• Aryl, allyl and some alkyl
radicals (refs 4 and 5)
C–B
90 kcal mol–1
>>
Thestrategythat wedescribeherewasconceived withastrongdesire
to make use of the native chemical reactivity1 of nitrogen-rich hetero-
cycles rather than attempting to override it with pre-functionalization
(Fig. 1a). Minisci’s pioneering workdemonstratedthe abilityof hetero-
cycles to react with certain alkyl and acyl radicals2 (derived from
carboxylic acids and halides (Fig. 1b)). This form of innate C–H func-
tionalization, however, is limited to a subset of alkyl and acyl donors,
and often requires higher temperatures (for example, greater than
70 uC), transition-metal additives and strongly oxidizing conditions3.
In 2010, it was reported that aryl boronic acids can be used as aryl
radical precursors for heterocycle functionalization4. Later, it was
shown that alkyl boronic acids and trifluoroborate salts can serve as
radical precursors5,6. In 2011, it was demonstrated that sodium trifluo-
romethanesulphinate, a reagent extensively studied by Langlois8, was
capable of trifluoromethylating heterocycles via a radical mechanism7.
Shortly thereafter, a procedure was described for difluoromethylation
that relied upon the use of a zinc-derived sulphinate salt9.
Zinc sulphinate salts are easily prepared, bench-stable, free-flowing
solids (with the exception of zinc triethyleneglycolsulphinate (TEGS; F)
(Fig. 1c)) that show remarkably enhanced reactivity compared with
sodium-derived analogues in radical additions to heterocycles (see
below). Here we describe a modular, innate C–H functionalization of
heterocycles using zinc sulphinate salts following a mild and practical
reaction protocol. We use a zinc bis(alkanesulphinate) salt toolkit,
much like available toolkits for cross-coupling chemistry, for the direct
O
S
Zinc sulphinate salts
• CF3, CF2H, CH2F and some alkyl
radicals (c and Table 1)
C–S
65 kcal mol–1
R
OH
R–CO2H
or
R–B(OH)2
O
O
c
Me
N
Me
N
(R–SO2)2Zn
MeN
O
MeN
NR
R
X
2–
N
N
[Ag], S2O8
N
Me
Caffeine (1)
O
N
Me
Zn
The (RSO2)2Zn toolkit was prepared by: R–SO2Cl
(R–SO2)2Zn
H2O
Sigma–Aldrich
catalogue number
Amount
prepared
R group
Acronym
(X-ray)
(X-ray)
-CH2CF3
-CH2F
-CH(CH3)2
-(CH2CH2O)3CH3
>500 g
>500 g
>100 g
37 g
>200 g
20 g
L510106
L510084
L511234
—
L511161
—
-CF3
-CF2H
TFMS (A)
DFMS (B)
TFES (C)
MFMS (D)
IPS (E)
TEGS (F)
Figure 1
|
Development of a reagent toolkit for an innate C–H
functionalization of heterocycles. a, Comparison of different methods of
heterocycle functionalization. b, Evolutionof the radical precursor. c, Invention
functionalization of a variety of heterocycles, all of which result in of new reagents for heterocycle functionalization.
1Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. 2Department of Chemistry, La Jolla Laboratories, Pfizer Inc., 10770 Science
Center Drive, San Diego, California 92121, USA.
*These authors contributed equally to this work.
6
D E C E M B E R 2 0 1 2 | V O L 4 9 2 | N A T U R E | 9 5
Macmillan Publishers Limited. All rights reserved
©2012

RESEARCH LETTER
reagent class that will permit the rapid diversification of heterocycles with hydroxymethyl (CH2OH) and methoxymethyl (CH2OCH3)
using an operationally simple protocol10. Functionalization using zinc groups25. However, monofluoromethylation methods are limited and
bis(alkanesulphinate) salts affords a marked improvement over functio- less well studied compared with trifluoromethylation and are typically
nalization with sodium-based sulphinate salts7 and is a generalization of introduced using ‘auxiliary’ approaches23, for example appending a
the zinc difluoromethanesulphinate chemistry developed previously9.
We identified a modular set of zinc sulphinate salts as being highly
desirable for the installation of medicinally relevant moieties (Fig. 1c):
zinc trifluoromethanesulphinate (TFMS; A), zinc difluoromethanesul-
phinate (DFMS; B), zinc trifluoroethanesulphinate (TFES; C), zinc
monofluoromethanesulphinate (MFMS; D), zinc isopropylsulphinate
(IPS; E), and zinc triethyleneglycolsulphinate (TEGS; F). The fluor-
oalkyl and alkyl groups that we wish to introduce hold privileged posi-
tions in drug discovery and are described in detail below.
The CF3 group is an excellent bioisostere of a methyl group because
the former is similar in size to the latter but does not suffer metabolic
oxidation11. It can also be used to tune the steric and electronic properties
of a known scaffold, and to grant favourable physicochemical attributes
to a lead target12,13. For these reasons, trifluoromethylation methodo-
logy has received much attention, with nucleophilic CF3 reagents14
(for example carbonyl functionalization), electrophilic CF3 reagents14
(for exampleenolate functionalization) and cross-coupling procedures
dominating arene functionalization15,16. (Metal-catalysed C–H activa-
tion for trifluoromethylation is also known17.) However, the trifluoro-
methylationof heterocycles is lesscommonowing to substrate-mediated
reagent or catalyst deactivation in these strongly basic, acidic or transi-
tion-metal-catalysed reactions.
To fill this gap in methodology, we have begun to study a radical-
based approach to trifluoromethylation7. Although the introduction
of the CF3 group by a radical pathway is known, reagents that achieve
this radical transformation are difficult to handle and are toxic (CF3I
(ref. 18), a gas), ozone-depleting (CF3Br (ref. 19), a gas) or corrosive
(CF3SO2Cl (refs 20, 21), a low-boiling liquid). Furthermore, CF3CO2H
does not generate radicals under Minisci conditions, and CF3B(OH)2, as
an analogy to borono-Minisci chemistry, is an unknown chemical spe-
cies (other CF3–boron sources such as CF3–B(OMe)3K and CF3–BF3K
are not viable radical precursors7). Although sodium trifluoromethane-
sulphinate (CF3SO2Na, a stable solid) addressed many of the above
difficulties for heterocycle trifluoromethylation, TFMS (A) was found
to be superior in terms of both stability and reactivity (47% yield was
obtained for a reaction of pentoxifylline (2) with CF3SO2Na in 2.5:1
CH2Cl2:H2O at room temperature for 48 h (ref. 7), 79% yield was
obtained for a reaction of pentoxifylline (2) with TFMS in 2.5:1
CH2Cl2:H2O at room temperature for 3 h (Table 1) and 99% yield was
obtained for a reaction of 2 with TFMS in 2.5:1 CH2Cl2:H2O at 50 uC for
3 h; also see comparisons of reaction conversions for various substrates
in Supplementary Information).
fluoro(phenylsulphonyl)methyl group and then removing the phenyl-
sulphonyl group26. The generation of a monofluoromethyl radical is
almost unknown, with only one report made on its characterization
by a matrix reaction of bromofluoromethane with alkali metals, without
demonstration of synthetic applicability27. As fluoroacetic acid (CH2F-
CO2H) cannot generate radicals under standard Minisci conditions, a
practical CH2F radical precursor and its application to synthetic che-
mistry is required; MFMS (D) is a new reagent devised for this purpose.
The ability to add steric bulk and lipophilicity where needed may
prove valuable when probing for structure–activity relationships or
when blocking metabolically labile positions. Methods for the direct
introduction of this hindered group include the use of toxic isopro-
pylmercurial reagent ((CH3)2CH-HgCl (ref. 28)) or the use of air- and
water-sensitive isopropyllithium or isopropylmagnesium chloride.
Furthermore, the use of (CH3)2CH-CO2H or (CH3)2CH-I with the
Minisci protocol on caffeine (1) did not afford the desired product at
room temperature or higher temperatures. A ‘programmed’ approach
to installing an isopropyl group is often low-yielding and problematic
using Suzuki- or Negishi-type couplings (with a few notable excep-
tions29) and we therefore designed an ‘innate’ approach using IPS (E).
Ethylene glycol units are excellent solubilizing units, and the utility
of poly(ethylene glycol) chains in drug delivery has been extensively
investigated30. As a proof of concept for the appendage of poly(ethy-
lene glycol) units onto heterocycles, we planned to introduce a shorter,
tri(ethylene glycol), chain that might retain the ability to increase the
hydrophilicity of a lead target. Methods to directly append an oligo
(ethylene glycol) unit onto heterocyclic frameworks are unknown, and
TEGS (F) was therefore devised.
The ability to incorporate fluoroalkyl, alkyl and alkoxyalkyl groups
into heterocyclic frameworks is highly desirable; however, until now
the chemistry to access substituted heterocycles rapidly has been
underdeveloped and of limited scope. The power of the zinc sulphinate
toolkit is demonstrated here with a synthesis of an exemplary set
of medicinally relevant heterocycles (.50 examples), most of which
represent new chemical entities.
As shown in Table 1, we used an operationally simple procedure to
functionalize xanthines (1 and 2), pyridines (3 and 4), quinoxalines
(5), pyrimidines (6), pyridazines (7) and pyrroles (8): the heterocycle
substrate and the zinc sulphinate salt were combined with a mixture of
organic solvent and water and cooled in an ice-water bath, tert-butyl
hydroperoxide (TBHP) was added and this mixture was warmed to
room temperature or 50 uC. Exclusion of air or purification of solvents
is unnecessary, and the reaction flask is sealed only with a plastic cap to
prevent solvent evaporation. Fluoroalkylated zinc sulphinate reagents
(A–D) performed best in halogenated solvents such as CH2Cl2,
ClCH2CH2Cl, perfluorotoluene and perfluorohexane, whereas alky-
lated zinc salts (E and F) reacted more favourably in DMSO or in an
electron-rich aromatic solvent such as anisole. For substrates that
showed low conversion, addition of one or more of the following
The CF2H group can act as a lipophilic hydrogen-bond donor and
has been used in bioisostere design variously to mimic a thiol, a hydro-
xamic acid, a hydroxyl and an amide11. Although the CF2H group can
be formed using (diethylamino)sulphur trifluoride on an aldehyde and
can be introduced using (trimethylsilyl)difluoromethane22 or other
difluoromethyl precursors23, direct difluoromethylation strategies on
heterocycles had not been explored before the invention of DFMS9 (B).
The CH2CF3 group is an excellent bioisostere of an ethyl group and was performed: zinc sulphinate salt, TBHP or trifluoroacetic acid.
acts as a mild electron-withdrawing group (trifluoroethanol is about 3.5
orders of magnitude more acidic than ethanol). Appendage of the
CH2CF3 group is typically achieved by multistep strategies (such as
nucleophilic addition of CF3 into an aldehyde followed by deoxygena-
tion), and a catalytic cross-coupling method for this purpose was
reported only recently24. A direct, free-radical-based approach for the
introduction of the CH2CF3 group was unknown, and therefore TFES
(C) was developed to fill this gap in methodology.
Perhaps the most notable aspect of C–C bond formation using zinc
sulphinate chemistry is the mildness of the reaction conditions. As
shown in Table 1, reactive groups such as nitriles, ketones and esters
are tolerated. The level of functional group compatibility can be extended
even to reactive heteroaryl halides, free carboxylic acids and boronate
esters, three groups of particular utility in pharmaceutical chemistry
owing to the ease of further functionalization via cross-coupling
methodsor amidebond formation(Fig. 2a). Thesegroups are typically
Much like the CF3 group, the CH2F group can act as a useful bio- incompatible with most organic reactions, much less C–H functiona-
isostere of a methyl group because the fluorine atom can also pre- lization strategies; however, under our reaction conditions, simple
vent metabolic oxidation owing to its electron-withdrawing effect. pyridine building blocks bearing a reactive chloro (9), pinacolato-
Furthermore, the CH2F group has also been considered bioisosteric boron (10) or carboxylic acid (11) moiety can be functionalized with
9 6
|
N A T U R E
|
V O L 4 9 2
|
6
D E C E M B E R 2 0 1 2
Macmillan Publishers Limited. All rights reserved
©2012

LETTER RESEARCH
Table 1
|
Substrate scope of the zinc sulphinate salt toolkit
O
S
TBHP
Het
Het
+
H
R
Zn
O
R
2
2.5:1 solvent:water*
Zinc sulphinate salt
Open flask, operational simplicity, .50 examples
Heterocycle
Zn salt, R
CF3 (A)
CF2H (B)
CH2CF3 (C)
CH2F (D)
CH(CH3)2 (E)
(CH2CH2O)3CH3 (F)
1
89 (100){
73 (57){11
51#
80#
41**
40{{
O
1A
1B
1C
1D
1E
1F
Me
N
MeN
H
N
O
O
N
Me
O
2
79 (100){
72 (41){11
44#
75#
37**
49{{
2A
2B
2C
2D
2E
2F
Me
N
4
N
H
Me
N
O
N
Me
H
3
4
35 (77){
[4:1 C2:C3]
3A
66 (100){
[only C2]
3B
18 (85)#
[4:1 C2:C3]
3C
73"{{
471
41{{
[only C2]
3F
[17:1 C2:C2&C6] [C2:C2&C6 1.4:1]
6
O
3D
3E
N
2
3
OEt
H
H
O
H
N
66 (65){11
[2.3:1 C6:C2] [C2:C6:C4 3:2:1]
60 (96){
33#
[1.4:1 C6:C4]
4C
NR
41{{
[only C6]
4E
NR
4
Br
4A
4B
4D
4F
Me
2
6
H
N
H
N
N
H
5
6
7
75 (100){
[5 products]
5A
50 (67){
31 (77){
56#
43**
32**
5B
5C
5D
5E
5F
Me
H
H
||
||
42 (44)
21 (44)
21**
[only C5]
6C
NR
46**
[2.1:1 C4:C5]
6E
16{{
[3.4:1 C4:C5]
6F
5
4
[2.7:1 C4:C5]
[1.6:1 C4:C5]
6A
6B
6D
NC
H
N
H
||
||
45 (90)
57 (71)
NR
NR
49**
[10:1 C4:C5]
7E
32 (38){{
[only C4]
7F
[only C4]
[6:1 C4:C5]
4
OMe
7A
7B
7C
7D
5
N
N
Cl
O
8
76 (91){
[7.4:1 C2:C5]
8A
65 (100){
[only C2]
8B
58**
[1.4:1 C2:C5]
8C
401
[only C2]
8D
17**
[only C2]
8E
10 (43){{
[only C2]
8F
Me
H
5
2
H
N
Me
Isolated yields are shown. Percentage conversions by gas chromatography (GC) mass spectrometry are indicated in parentheses, and regioisomeric ratios are shown in square brackets. Compounds 1A, 2A, 3A, 4A
and 5A have been previously synthesized with Langlois reagent (ref. 7), and compounds 1B, 2B, 3B, 4B, 5B and 8B have been previously prepared using DFMS (ref. 9) and are included for completeness; all other
compounds in this table are new.
* Standard conditions involve heterocycle (1.0 equiv.), zinc salt (2.0–3.0 equiv.), TBHP (3.0–5.0 equiv.) and solvent:water (2.5:1) at a specified temperature for a period of 3–12 h.
||
Solvent and temperature: {CH2Cl2, RT; {ClCH2CH2Cl, RT; 1ClCH2CH2Cl, 50 uC; perfluorohexane, RT; "perfluorotoluene, RT; #perfluorotoluene, 50 uC; **DMSO, 50 uC; {{anisole, 50 uC (the reaction time for
anisole is 0.5–96 h; see Supplementary Information).
{{ TFA was used as an additive.
11 When the GC percentage conversion is lower than the isolated yield, it signifies that only one addition of Zn salt was made for the ‘GC yield reaction’, but that a second addition of Zn salt and TBHP was performed
after 12 h for the ‘isolated yield reaction’.
Et, ethyl; Me, methyl; NR, no reaction; RT, room temperature (25 uC); TBHP, tert-butyl hydroperoxide; TFA, trifluoroacetic acid.
and was previously prepared from 4-chloro-2-pyridinecarbaldehyde
(US$432 per gram fromMatrixScientific) using (diethylamino)sulphur
trifluoride or from 2-picolinic acid using a laborious six-step protocol;
the zinc sulphinate procedure allowed the synthesis of 12 from a
cheap precursor (US$1.1 per gram from Oakwood Products), 4-
chloropyridinium hydrochloride (9).
CF3 or CF2H groups. In particular, carboxylic acid 11 is a quintes-
sential example of the unique chemoselectivity and mildness of the
reaction conditions, because Minisci or borono-Minisci conditions
would not leave the carboxylic acid unit intact. It is of note that the
modest yields observed in these reactions are due to difficulties in
product isolation, for example the high volatilityof difluoromethylated
product 12. It is of further note that 12 is commercially available but is
To further test the specificity of this transformation to react at the
prohibitively expensive (US$3,500 per gram from Accel Pharmtech) position defined by the innate reactivity of the given heterocycle, we
6
D E C E M B E R 2 0 1 2 | V O L 4 9 2 | N A T U R E | 9 7
Macmillan Publishers Limited. All rights reserved
©2012

RESEARCH LETTER
performed a one-pot sequential C–H functionalization of the anti- lipophilic derivatives of hydrophilic molecules such as dihydroquinine
and 6-chloropurine, because the isolation of water-soluble inter-
mediates can be avoided and only the lipophilic bis-substituted pro-
duct is isolated.
malarial drug dihydroquinine (15; Fig. 2b). Because our previous stud-
ies suggested that electrophilic radicals add to the C7 position of 15
(ref. 7) and that nucleophilic radicals add to the C2 position of 15
(ref. 9), we expected 15 to react sequentially when an electrophilic
and a nucleophilic radical were added in one pot. To test this, we added
TFMS (A) and then IPS (E) to a reaction vessel containing 15, after
which difunctionalized dihydroquinine derivative 16 was isolated
in 30% yield. The scope of this sequential functionalization was further
extended to examples including pyridines (17 and 18) and purines
(19). This strategy is particularly useful for the construction of
Finally, the versatile nature of this transformation is demonstrated
by the ability to carry out difluoromethylation and trifluoromethyla-
tion in unconventional media (conversion to product confirmed
by high-performance liquid chromotography), including cell lysate
(Fig. 2c, i), tea (Fig. 2c, ii) and a Tris buffer solution in the presence
of a serine-based b-lactamase (Fig. 2c, iii), which retained its functional
activity after reisolation. These findings may have important implica-
tions in the area of bioconjugation10.
Although zinc sulphinate chemistry can provide a great number of
new chemical entities that are difficult or impossible to access in other
ways, and yet have high levels of chemoselectivity, this procedure,
much like other methods, is not without limitations. For instance,
some nucleophilic radicals gave markedly lower yields when reacting
with certain electron-rich substrates, for example a 17% yield in the
reaction of IPS (E) with pyrrole 8 (Table 1). We found that many
solvents sometimes had to be screened to achieve the desired reaction
(for example for MFMS (D)). Nevertheless, we believe that the prac-
ticality, versatility and functional group tolerance of this innate func-
tionalization of heterocycles makes it a valuable addition to the range
of C–H functionalization methods that can be used to construct phar-
maceutically important targets. In addition, comparison of traditional
programmed approaches (of which none exist for three of the six salts
described in Table 1) with the synthesis of compounds in Table 1 and,
especially, those in Fig. 2 shows that it would be extremely difficult to
devise a faster, simpler or cheaper way to make such molecules.
In most contexts of discovery chemistry, reactions that can be con-
ducted open to the air on unprotected, late-stage molecules in 10–50%
yield are preferable to time-intensive, multistep routes, especiallywhen
the overall yield of such routes (for instance a typical sequence of
protection, lithiation, iodination, cross-coupling and deprotection) is
comparable to this direct approach. It is of note that 50 of the 52
compounds reported here have not been prepared before (or have only
previously been described by our laboratory7,9; several other methods
are listed in compound databases but no preparations are reported).
Zinc sulphinate chemistry is not limited to the six salts presented
above. Salts have also been prepared for the transfer of CH2Cl,
CH2CO2Me, cyclohexyl (for example, see 18 in Fig. 2b) and perfluo-
roalkyl (for example C6F13) groups, and the extent of their scope is
currently being examined (Supplementary Information).
a
Bpin
TFMS, TBHP
R
Cl
CH2Cl2/H2O
50% (94%)*
N
CF3
CO2H
DFMS,
TBHP
13
51% (85%)*
HF2C
N
N
•HCl
TFMS, TBHP
9: R = Cl
12
(US$3,500 g–1
or 6-step
synthesis from
2-picolinic acid)
(US$1.1 g–1
10: R = Bpin
11: R = CH2CO2H
)
CH2Cl2/H2O
57%
N
CF3
14
b
Et
Et
N
N
i. TFMS, TBHP,
TFA, CH2Cl2/H2O
OH
OH
MeO
MeO
ii. IPS, TBHP
30%
Me
Me
2
7
2
7
F3C
N
(one pot)
H
N
H
16
Dihydroquinine
(15)
RE+
RNu–
CO2H
Cl
CO2Et
H
N
Me
Me
5
N
2
6
N
Cy
HF2C
N
HF2C
N
HF2C
N
CF3
18 (22%)†
19 (23%)
17 (20%)
We have described the invention of a zinc sulphinate toolkit con-
taining ten different groups (CF3, CF2H, CH2CF3, CH2F, CH(CH3)2,
(CH2CH2O)3CH3, CH2Cl,CH2CO2CH3, cyclohexylandC6F13)forthe
simple and rapid diversification of heterocycles. Four of these reagents
are currently commercially available from Sigma-Aldrich (TFMS,
catalogue no. L510106; DFMS, catalogue no. L510084; TFES, catalogue
no. L511234; IPS, catalogue no. L511161). Particular advantages of this
chemistry include (1) the superiority of zinc over sodium alkylsulphi-
nates, which led to the identification of a highly active counter-cation
and allowed for an efficient radical generation from alkylsulphinates;
(2) the mildness of the reaction conditions, which tolerated highly
sensitive functional groups such as chloro and boryl groups; (3) a
different, transition-metal-free mode of radical generation compared
with Minisci chemistry, as benzylic carboxylic acids were tolerated;
(4) the feasibility of a sequential, one-pot operation that allowed for
a site-selective bis-alkylation of heterocycles using two different alky-
lating agents; and (5) the ability to conduct these reactions under
open air, without organic co-solvent and in the presence of extensive
impurities in the reaction medium, which may have potential applica-
tions in bioconjugation.
c
O
O
Me
Me
N
N
MeN
O
TFMS or DFMS
TBHP, RT
MeN
O
R
N
N
N
Me (1)
N
Me (1A or 1B)
i (TFMS)
ii (DFMS)
iii (DFMS)
1M Tris buffer containing
Cell
lysate
β-lactamase
Oolong tea
Figure 2
|
Chemoselectivity, rapid diversity and complexity generation, and
practical utility. a, Functional group tolerance and cost-effective synthesis of
12. Bpin, pinacolatoboron. *Percentage conversion as observed by gas
chromatography mass spectrometry analysis. b, One-pot sequential addition in
water and under air. Cy, cyclohexyl. {Six per cent yield of the C5-cyclohexyl
Thischemistryhasalreadybeen‘field-tested’ and is now widely used
for medicinal chemistry at Pfizer; several of the building blocks
isomer was also obtained. c, Operational simplicity in unconventional media. reported in this work are currently in use there (3–5, 7, 13 and 14).
9 8
|
N A T U R E
|
V O L 4 9 2
|
6
D E C E M B E R 2 0 1 2
Macmillan Publishers Limited. All rights reserved
©2012

LETTER RESEARCH
13. Kirk, K. L. Fluorination in medicinal chemistry: methods, strategies, and recent
developments. Org. Process Res. Dev. 12, 305–321 (2008).
14. Ma, J.-A. & Cahard, D. Strategies for nucleophilic, electrophilic, and radical
trifluoromethylations. J. Fluor. Chem. 128, 975–996 (2007).
15. Cho, E. J. et al. The palladium-catalyzed trifluoromethylation of aryl chlorides.
Science 328, 1679–1681 (2010).
16. Morimoto, H., Tsubogo, T., Litvinas, N. D. & Hartwig, J. F. A broadly applicable
copper reagent for trifluoromethylations and perfluoroalkylations of aryl iodides
and bromides. Angew. Chem. Int. Ed. 50, 3793–3798 (2011).
17. Wang, X., Truesdale, L. & Yu, J.-Q. Pd(II)-catalyzed ortho-trifluoromethylation of
arenes using TFA as a promoter. J. Am. Chem. Soc. 132, 3648–3649 (2010).
18. Kino, T. et al. Trifluoromethylation of various aromatic compounds by CF3I in the
presence of Fe(II) compound, H2O2 and dimethylsulfoxide. J. Fluor. Chem. 131,
98–105 (2010).
19. Qi, Q., Shen, Q. & Lu, L. Polyfluoroalkylation of 2-aminothiazoles. J. Fluor. Chem.
133, 115–119 (2012).
In many cases, building blocks that would be regarded as ‘low priority’
at Pfizer owing to prohibitively high cost or lengthy synthetic routes
are now easily accessible. The extreme operational ease, functional
group tolerance and ability to run reactions in unconventional media
open to air bode well for the widespread application of zinc sulphinate
salts in chemical synthesis. As a further outlook for the utility of innate
heterocycle functionalization, zinc sulphinate reagents could poten-
tially be used to cap metabolically susceptible positions in bioactive
molecules and to identify the most reactive sites of a given heteroarene.
The development of such a ‘profiling system’, providing a set of empir-
ically determined reactivity rules to organic chemists, is a topic of
ongoing research in our laboratory.
20. Kamigata, N., Ohtsuka, T., Fukushima, T., Yoshida, M. & Shimizu, T. Direct
perfluoroalkylation of aromatic and heteroaromatic compounds with
perfluoroalkanesulfonyl chlorides catalysed by a ruthenium(II) phosphine
complex. J. Chem. Soc. Perkin Trans. I 1339–1346 (1994).
21. Nagib, D. A. & MacMillan, D. W. C. Trifluoromethylation of arenes and heteroarenes
by means of photoredox catalysis. Nature 480, 224–228 (2011).
22. Fier, P. S. & Hartwig, J. F. Copper-mediated difluoromethylation of aryl and vinyl
iodides. J. Am. Chem. Soc. 134, 5524–5527 (2012).
23. Hu, J., Zhang, W. & Wang, F. Selective difluoromethylation and
monofluoromethylation reactions. Chem. Commun. 7465–7478 (2009).
24. Zhao, Y. & Hu, J. Palladium-catalyzed 2,2,2-trifluoroethylation of organoboronic
acids and esters. Angew. Chem. Int. Ed. 51, 1033–1036 (2012).
25. Mu¨ller, K., Faeh, C. & Diederich, F. Fluorine in pharmaceuticals: looking beyond
intuition. Science 317, 1881–1886 (2007).
26. Li, Y. et al. Stereoselective nucleophilic monofluoromethylation of N-(tert-
butanesulfinyl)imines with fluoromethyl phenyl sulfone. Org. Lett. 8, 1693–1696
(2006).
27. Raymond, J. I. & Andrews, L. Matrix reactions of fluorohalomethanes with alkali
metals. Infrared spectrum and bonding in the monofluoromethyl radical. J. Phys.
Chem. 75, 3235–3242 (1971).
28. Russell, G. A., Guo, D. & Khanna, R. K. Alkylation of pyridine in free radical chain
reactions utilizing alkylmercurials. J. Org. Chem. 50, 3423–3425 (1985).
29. Han, C. & Buchwald, S. L. Negishi coupling of secondary alkylzinc halides with aryl
bromides and chlorides. J. Am. Chem. Soc. 131, 7532–7533 (2009).
30. Knop, K., Hoogenboom, R., Fischer, D. & Schubert, U. S. Poly(ethylene glycol) in
drug delivery: pros and cons as well as potential alternatives. Angew. Chem. Int. Ed.
49, 6288–6308 (2010).
METHODS SUMMARY
All reactions were carried out under an atmosphere of air. Reagents were of the
highest commercial quality and were used without further purification, unless
otherwise stated. Yields refer to chromatographically and spectroscopically (1H
NMR) homogeneous material, unless otherwise stated. Reactions were monitored
by thin-layer chromatography carried out on 0.25-mm E. Merck silica plates (60F-
254), using ultraviolet light as the visualizing agent and KMnO4 as a developing
agent. For full experimental details and procedures for all reactions performed and
full characterization (1H, 13C and 19F NMR, high-resolution mass spectrometry,
infrared spectroscopy, melting point and Rf value) of all new compounds, see Sup-
plementary Information.
Full Methods and any associated references are available in the online version of
the paper.
Received 1 June; accepted 16 October 2012.
Published online 28 November 2012.
1. Bru¨ckl, T., Baxter, R. D., Ishihara, Y. & Baran, P. S. Innate and guided C–H
functionalization logic. Acc. Chem. Res. 45, 826–839 (2012).
2. Minisci, F., Vismara, E. & Fontana, F. Recent developments of free-radical
substitutions of heteroaromatic bases. Heterocycles 28, 489–519 (1989).
3. Duncton, M. A. J. Minisci reactions: versatile CH-functionalizations for medicinal
chemists. Med. Chem. Comm. 2, 1135–1161 (2011).
4. Seiple, I. B. et al. Direct C–H arylation of electron-deficient heterocycles with
arylboronic acids. J. Am. Chem. Soc. 132, 13194–13196 (2010).
5. Fujiwara, Y. et al. Practical C–H functionalization of quinones with boronic acids.
J. Am. Chem. Soc. 133, 3292–3295 (2011).
6. Molander, G. A., Colombel, V. & Braz, V. A. Direct alkylation of heteroaryls using
potassium alkyl- and alkoxymethyltrifluoroborates. Org. Lett. 13, 1852–1855 (2011).
7. Ji, Y. et al. Innate C–H trifluoromethylation of heterocycles. Proc. Natl Acad. Sci. USA
108, 14411–14415 (2011).
Supplementary Information is available in the online version of the paper.
Acknowledgements We thank D.-H. Huang and L. Pasternack for NMR spectroscopic
assistance, A. Schuyler and W. Uritboonthai for mass spectrometry assistance and
D. Cayer for the analysis of the b-lactamase activity. Financial support for this work was
provided by the US NIH/NIGMS (GM-073949), the Uehara Memorial Foundation
(postdoctoral fellowship for Y.F.), the US–UK Fulbright Commission (postdoctoral
fellowship for F.O.), Aarhus University, OChem Graduate School, CDNA, CFIN and
NABIIT (fellowship for E.D.F.), the US NIH (graduate fellowship for R.A.R.) and Pfizer Inc.
(postdoctoral fellowship for R.D.B.).
8. Langlois, B. R., Laurent, E. & Roidot, N. Trifluoromethylation of aromatic
compounds with sodium trifluoromethanesulfinate under oxidative conditions.
Tetrahedr. Lett. 32, 7525–7528 (1991).
Author Contributions Y.F., J.A.D., D.D.D., R.A.R. and P.S.B. conceived the work; Y.F.,
J.A.D., F.O., E.D.F., D.D.D., R.A.R., R.D.B., B.H.,N.S. andM.R.C. performedthe experiments;
Y.F., J.A.D., F.O., E.D.F., D.D.D., R.A.R., R.D.B., B.H., N.S., M.R.C. and P.S.B. designed the
experiments and analysed the data; and F.O., R.A.R., Y.I. and P.S.B. wrote the
manuscript.
9. Fujiwara, Y. et al. A new reagent for direct difluoromethylation. J. Am. Chem. Soc.
134, 1494–1497 (2012).
10. Kolb, H. C., Finn, M. G. & Sharpless, K. B. Click chemistry: diverse chemical function
from a few good reactions. Angew. Chem. Int. Ed. 40, 2004–2021 (2001).
11. Meanwell, N. A. Synopsis of some recent tactical application of bioisosteres in drug
design. J. Med. Chem. 54, 2529–2591 (2011).
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 P.S.B. (pbaran@scripps.edu).
12. Purser, S., Moore, P. R., Swallow, S. & Gouverneur, V. Fluorine in medicinal
chemistry. Chem. Soc. Rev. 37, 320–330 (2008).
6
D E C E M B E R 2 0 1 2 | V O L 4 9 2 | N A T U R E | 9 9
Macmillan Publishers Limited. All rights reserved
©2012

RESEARCH LETTER
a second addition of Zn salt (2.0–3.0equiv.) and TBHP (3.0–5.0 equiv.) may be
added to drive the reaction further. On consumption of the starting material, the
reaction was partitioned between EtOAc (5.0 ml) and saturated NaHCO3 (5.0 ml)
or CH2Cl2 (5.0 ml) and saturated NaHCO3 (5.0 ml). The organic layer was sepa-
rated, and the aqueous layer was extracted with EtOAc or CH2Cl2 (33 5.0 ml).
The organic layers were dried with Na2SO4, concentrated and purified by
column chromatography on silica gel. We note that if the TBHP is added too
rapidly, the resulting exotherm can result in reduced yield and selectivity. This
is especially important on larger scales, where a syringe pump may be used to add
METHODS
Our standard procedure for the functionalization of heterocycles was as follows. A
solution of heterocycle (0.125–0.250 mmol, 1.0 equiv.) and Zn salt (2.0–3.0 equiv.)
in an organic solvent was cooled in an ice-water bath, and this was followed by the
slow addition of TBHP (70% solution in water, 54–179 ml, 3.0–5.0 equiv.) using an
Eppendorf pipette (metal needles should not be used as they decompose the
reagent) with vigorous stirring. The reaction mixture was warmed to room tem-
perature or 50 uC and monitored by thin-layer chromatography until reaction
completion. For substrates that do not achieve reaction completion in 12–24 h, the TBHP.
Macmillan Publishers Limited. All rights reserved
©2012