Palauchlor: A practical and reactive chlorinating reagent

Article abstract of DOI:10.1021/ja5031744

Unlike its other halogen atom siblings, the utility of chlorinated arenes and (hetero)arenes are twofold: they are useful in tuning electronic structure as well as acting as points for diversification via cross-coupling. Herein we report the invention of a new guanidine-based chlorinating reagent, CBMG or "Palauchlor", inspired by a key chlorospirocyclization en route to pyrrole imidazole alkaloids. This direct, mild, operationally simple, and safe chlorinating method is compatible with a range of nitrogen-containing heterocycles as well as select classes of arenes, conjugated π-systems, sulfonamides, and silyl enol ethers. Comparisons with other known chlorinating reagents revealed CBMG to be the premier reagent.

Full text of DOI:10.1021/ja5031744

Communication
pubs.acs.org/JACS
Palau’chlor: A Practical and Reactive Chlorinating Reagent
Rodrigo A. Rodriguez,† Chung-Mao Pan,†,§ Yuki Yabe,†,§ Yu Kawamata,† Martin D. Eastgate,‡
and Phil S. Baran*,†
†Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
‡Chemical Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States
S
* Supporting Information
ABSTRACT: Unlike its other halogen atom siblings, the
utility of chlorinated arenes and (hetero)arenes are
twofold: they are useful in tuning electronic structure as
well as acting as points for diversification via cross-
coupling. Herein we report the invention of a new
guanidine-based chlorinating reagent, CBMG or “Palau’-
chlor”, inspired by a key chlorospirocyclization en route to
pyrrole imidazole alkaloids. This direct, mild, operationally
simple, and safe chlorinating method is compatible with a
range of nitrogen-containing heterocycles as well as select
classes of arenes, conjugated π-systems, sulfonamides, and
silyl enol ethers. Comparisons with other known
chlorinating reagents revealed CBMG to be the premier
reagent.
nlike other aromatic halides, aryl chlorides have a
Udichotomous function in the areas of pharmaceuticals
(e.g., Plavix, Abilify, Lunesta),1−3 imaging (11C-raclopride),4
natural products (vancomycin, aureomycin),5,6 agrochemicals
(DDT, Dicofol),7 and materials science (Cl8-PTCDI, Cl16-
CuPc).8 Their presence confers molecules with both function and
functionalizability. Within the agrochemical and drug discovery
arenas, chlorination is usually motivated by a desire to enhance
biological properties in a similar vein to fluorination (but in
contrast to bromination or iodination). However, aryl chlorides
stand alone in their nearly limitless potential for diversification
using cross-coupling chemistry (like bromine and iodine but in
stark contrast to fluorine). In view of the widespread presence of
aryl chlorides, it is somewhat puzzling that modern methods for
direct chlorination still rely on age-old reagents. In this
communication, the invention of a new guanidine-based reagent
for the direct electrophilic chlorination of heteroaromatic
systems is reported. This reagent is highly reactive and stable
and can accomplish C−H chlorinations that conventional
reagents fail to achieve under identical conditions.
Figure 1. Invention of CBMG (“Palau’chlor”) inspired by the pyrrole
imidazole alkaloid family of natural products. Notes: aStarting material
comparable in cost to the NCS precursor (succinimide = US $0.144/g
from Aldrich). bAdditional data on imidazo[1,2-a]pyrazine are included
in the Supporting Information (SI).
Direct methods for aromatic C−H chlorination can be
classified into three main modes (Figure 1A), some of which
present drawbacks: (1) electrophilic aromatic substitution
(SEAr),9,12−19 where reagents can be too reactive, unselective,
or, conversely, unreactive without the presence of strong
electron-donating groups on the aromatic system; (2) hydro-
gen−metal exchange (specifically, directed ortho metalation)
followed by trapping with a Cl+ source,10 which can be efficient
and regioselective but requires the use of a strong base and a
directing group; (3) transition-metal-catalyzed C−H activation
methods, which are emerging as useful tools with regioselectivity
that is often complementary to classical methods, though the
substrate scope can be limited.11
Innate C−H chlorination (SEAr) is perhaps the oldest method
to prepare aromatic chlorides and can be generalized into two
main classes: reactive and practical. Reactive SEAr methods
Received: March 29, 2014
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
Table 1. Scope of C−H Chlorination of Heteroarene Substrates
a
b
Conditions: heterocycle (1.0 equiv), NCS or CBMG (1.2 equiv), CHCl3 (0.1 M). Isolated yields are shown. Decomposition observed with most
c
d
e
f
aldehydes. CBMG (2.2 equiv). CBMG (2.2 equiv), 50 °C, 1 h. CH3CN. Product could be purified only by filtration (NCS crude reaction shown
g
as 1H NMR yield). CH3CN, CBMG (2.2 equiv); nonactivated pyridines, 2-hydroxypridine, and 2-(tert-butoxy)pyridine were not reactive substrates
h
i
j
under these conditions. 30 min (NCS at 12 h = 52%). Product was unstable. 1-Acetylindole was chlorinated by CBMG and NCS in lower yields
(28% and 3%, respectively).
utilize some of the most traditional chlorinating reagents (Cl2 or
SO2Cl2), which generally have safety liabilities that limit their
application because of their aggressive reactivity.12 Mild methods
use substantially less reactive reagents [N-chlorosuccinimide
(NCS) and 1,3-dichloro-5,5-dimethylhydantoin (DCDMH)].
While these reagents (e.g., NCS) are inexpensive, easy to handle,
and therefore practical, their reduced reactivity can limit their
application.13,14 Often operating with radical-based mechanisms,
tBuOCl serves as a valuable chlorinating reagent,15 but its
reactivity is variable on arenes16 and it is dangerously light-
sensitive (releases MeCl),15 heat-sensitive (releases Cl2),17 and
moisture-sensitive (ignition).18 Other chlorinating reagents
exist,19 but many of these are toxic (e.g., PhSeCl,19a), explosive
(e.g., TiCl4/CF3CO3H19b), hygroscopic (e.g., NCS/ZrCl419c),
or strongly acidic (e.g., SbCl5,19d N-chloramines in neat acids19e);
hence, many chlorination reagents and methods have significant
liabilities that limit their application in organic chemistry.
During a study of the mechanism of the intramolecular
chlorospirocyclization of 1 to 3 (Figure 1B),20 it was discovered
that a stable and hitherto unisolated N-chloroguanidine, 2, was
the functioning chlorinating agent. This finding inspired broad
exploration into reagents of similar structure, such as 4−7, which
could function as potentially powerful chlorinating reagents. A
particularly promising gauge of the chlorinating ability of these new
reagents was the observation that benzenesulfonamide was N-
chlorinated in quantitative yield whereas tBuOCl or NCS failed to
deliver any product (vide infra).
variation of the pendant acyl groups on the guanidine led to
the identification of chlorobis(methoxycarbonyl)guanidine (7,
CBMG, “Palau’chlor”) as the optimal chloroguanidine reagent.
Subsequent analysis has shown CBMG to be an air-stable, bench-
stable, free-flowing powder. Initial assessment of the thermal
stability of CBMG by differential scanning calorimetry (DSC)
showed no thermal events below 100 °C, with a calculated
adiabatic decomposition temperature over 24 h (ADT24) of >80
°C and a projected stability of greater than 1 year at rt (at 25 °C
under isothermal conditions).
We were interested in seeing how this first-in-class reagent
compared to existing chlorinating reagents, and thus, we
screened a range of chlorinating agents and compared their
reactivities with 10 to that of CBMG (Figure 1C). The results of
our studies indicated that CBMG furnishes a higher yield of
product than Cl2, SO2Cl2, and tBuOCl while being as cost-
effective as NCS. CBMG can be generated in large quantities and
has now been commercialized through Sigma-Aldrich (CBMG,
Palau’chlor, cat. no. 792454).
With this new chloroguanidine reagent in hand, the scope of
heteroarene C−H chlorination was evaluated (Table 1).
Numerous substrates showed unmatched reactivity with
CBMG compared with NCS under identical conditions (1.2
equiv of chlorinating reagent). Although CBMG showed slightly
better solubility in CHCl3 at rt compared with NCS, its
performance was higher regardless of the solvent employed.21
Thus, imidazoles (11, 12), pyrroles (13−16), pyrazoles (17, 18),
indoles (21−25), and other heterocycles (19, 20, 26−29) could
all be cleanly chlorinated.
With a focus on heteroaromatic chlorination, clotrimazole
(10) emerged as an ideal model substrate for comparing the
reactivities of chlorinating agents, since NCS failed to deliver any
chlorinated product at room temperature (rt). Systematic
In most cases, substrates with multiple potential reaction sites
exhibited high levels of regioselectivity, producing a single
B
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isomer. In cases where a single regiosiomer was not produced,
bis-C−H chlorination was often observed (13−15, 20, 25). 2-
(Trichloroacetyl)pyrrole can be used as a versatile synthetic
intermediate to access either 4- or 5-functionalized pyrrole-2-
carboxamides.22 Most likely because of poor selectivity (over-
chlorination and potential polymerization using SO2Cl2),23 the
commercial availability of 16 is limited (Ryan Scientific Inc.; US
$390/g). Under the standard conditions, CBMG proved to be a
selective reagent, providing 16 in good yield. A key feature of
CBMG is the ease of post-reaction purification, leading to
efficient reagent recycling.24
Table 2. Chlorination of Non-Heteroarenes (Isolated Yields
Are Shown)
An investigation of the reaction rate was conducted using two
heteroarene substrates (Figure 2). Imidazo[1,2-a]pyrazine
a
Phenylsilane showed no reactivity toward CBMG at rt; chlorode-
a
Figure 2. Reaction rate and mechanistic study. Notes: The standard
boronation of 3-nitrophenylboronic acid gave no apparent difference
in yield compared with ref 32. One-pot operation: TMSOTf (3.0
b
conditions were employed using CBMG or NCS (1.2 equiv); yields
were recorded as 1H NMR yields using 1,2-dichloroethane as an internal
standard. bThe clotrimazole reaction was heated to 50 °C after it showed
no reactivity at rt.
equiv), DIPEA (3.0 equiv), CH2Cl2, then CBMG or NCS (1.5 equiv).
c
d
Inseparable mixture of regioisomers. GC yield after 12 h at 60 °C.
e
f
g
CBMG or NCS (2.2 equiv). (NCS at 50 °C, 12 h = 26%). CBMG
or NCS (2.0 equiv), DMF, rt, 48 h, preparative HPLC purification.
h
i
Chlorinating reagent (1.0 equiv), H+ (1.0 equiv). 1H NMR yields
j
(precursor to 19) and clotrimazole (10) are substrates that
show a representative contrast between CBMG and NCS. For
10, reaction with CBMG at rt gave a quantitative yield (1H
NMR) after 100 min, whereas NCS was completely unreactive at
rt. NCS reacted with 10 only after the reaction mixture was
heated to 50 °C. Similarly, imidazo[1,2-a]pyrazine reacted with
CBMG to give a quantitative yield (1H NMR) after 40 min at rt,
but only trace amounts had reacted with NCS after 40 min. It is
worth noting that the increased reactivity of NCS upon heating is
not sufficient to mimic the performance of CBMG, and in some
instances (e.g., 31) only trace chlorinated product was observed
after heating for a prolonged period.
To understand the mechanistic differences between CBMG
and NCS, the kinetic isotope effects (KIEs) were determined in
the reactions of anisole (36) and d8-36 with CBMG versus NCS
(see the SI). When 36 and d8-36 were monitored using GC, the
rates of chlorination with CBMG showed a normal KIE of 1.2,
which is only slightly greater than unity. This indicates that the
aromatic C−H bond is not likely to be broken in the rate-
determining step (RDS) (typical of SEAr). This is supported by
the fact that CBMG and NCS show identical KIEs of 1.2 on 36
and d8-36, wherein NCS has been previously shown to operate
by an SEAr mechanism with dearomatization as the RDS.
In addition to the heteroarene substrates listed in Table 1,
other organic substrates also displayed improved reactivity using
using CH3NO2 as an internal standard. Isolated yield after preparative
HPLC.
the described process with CBMG compared with NCS and
tBuOCl (Table 2). Chemoselective α-chlorination of a carbonyl
compound was achieved from the corresponding silyl enol ether
in a one-pot operation. Electron-rich conjugated π-systems and
sulfonamides were also competent substrates for direct C−H and
N−H chlorination. In view of the fact that CBMG is prepared
from tBuOCl and the similar N-chlorinated sulfonamide
Chloramine-T is prepared from in situ-generated NaOCl
(from NaOH and Cl2),25 it is somewhat puzzling that neither
benzenesulfonamide nor N-methylbenzenesulfonamide was
effectively chlorinated with either NCS or tBuOCl alone under
identical conditions.26
Furthermore, CBMG can be used in a complex setting. For
example, rotenone (a common pesticide)27 was selectively
chlorinated in the presence of an olefin to give 34.28 In an even
more extreme case of functional group tolerance, exposure of
vancomycin to the reaction conditions in N,N-dimethylforma-
mide (DMF) showed a 2-fold increase in C−H chlorination of
the electron-rich biaryl relative to NCS.29
After an extensive survey and attempted reproduction of
literature procedures,30 it was determined that regioselective
C
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Journal of the American Chemical Society
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chlorination (for landmark examples of regioselective bromina-
tion, see ref 29) of simple arenes remains an area in need of
improved technology, and CBMG may also benefit this area of
study. Although CBMG was found to react with anisole (36) at
elevated temperatures (Table 2A), it was also found that the
addition of 1.0 equiv of Brønsted acid significantly accelerates the
reaction.31 Thus, treatment of 36 with 1.0 equiv of CBMG and
1.0 equiv of trifluoroacetic acid (TFA) led to a 74% yield of
products with a remarkable 12:1 para:ortho selectivity (surpass-
ing all selectivities known).30 Furthermore, this reagent was
compared with a host of other chlorinating agents, which
demonstrated that CBMG/TFA is superior in regioselectivity
(Table 2B, entries 1−5). This dramatic effect was accentuated
when the acid was changed from TFA to HCl (1.0 equiv), where
a quantitative yield was obtained with 32:1 para:ortho selectivity
(Table 2B, entry 6). To showcase the ability of CBMG to
perform as a selective chlorinating reagent, Pavabid was
subjected to the CBMG protocol to give 37 as a single product
(Table 2B).
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reagent (7, CBMG, “Palau’chlor”) was invented by studying
the mechanism of a key chlorospirocyclization en route to
palau’amine. CBMG is comparable in both cost (raw materials
and high synthetic efficiency) and molecular weight to the classic
reagent NCS yet exhibits a reactivity profile that is equivalent to
or better than those of more aggressive reagents (SO2Cl2, Cl2,
tBuOCl) without sacrificing functional group tolerance. This
reactive yet practical reagent has been shown to outperform a
plethora of known chlorinating systems across a wide range of
substrate classes, leading to its commercialization by Sigma-
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(hetero)aryl chlorides bodes well for the use of 7 in many
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atoms (I, Br, F, Se, S, etc.) and in asymmetric synthesis are
subjects worthy of additional study.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, KIE complete data acquisition, DSC
analysis, and analytical data for all new compounds, including 1H
and 13C NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
(25) Shetty, M.; Gowda, T. B. Z. Naturforsch. 2004, 59, 63.
1
(26) See the SI for crude H NMR data using CBMG, NCS, and
tBuOCl on N-methylbenzenesulfonamide.
AUTHOR INFORMATION
(27) Haley, T. J. J. Environ. Pathol. Toxicol. 1978, 1, 315.
(28) Complementary halogenating reagents for olefin and polyene
cyclizations are available: Snyder, S. A.; Treitler, D. S.; Brucks, A. P. J.
Am. Chem. Soc. 2010, 132, 14303. The chloro version of this reagent
class (CDSC) was not a suitable arene chlorinating reagent in our hands.
(29) The site selectivity was compared with that of a known
regioselective bromination on vancomycin: Pathak, T. P.; Miller, S. J.
J. Am. Chem. Soc. 2012, 134, 6120. For another example of regioselective
bromination, see: Snyder, S. A.; Gollner, A.; Chiriac, M. I. Nature 2011,
474, 461.
■
Corresponding Author
pbaran@scripps.edu
Author Contributions
§C.-M.P. and Y.Y. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(30) See the SI for a list of literature protocols and attempted
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(a) van Tamelen, E. E.; Sharpless, K. B. Tetrahedron Lett. 1967, 8, 2655.
(b) Foo, K.; Newhouse, T.; Mori, I.; Takayama, H.; Baran, P. S. Angew.
Chem., Int. Ed. 2011, 50, 2716.
■
We are grateful to Dr. A. L. Rheingold, Dr. C. E. Moore, and Dr. J.
A. Golen for X-ray analysis, Dr. A. Okano for assistance with
vancomycin, Dr. Y. Ishihara and Mr. S. J. McKerrall for helpful
discussions, Mr. A. Fritz and Mr. A. Fakhoury for DSC analysis,
and the NSF (fellowship to R.A.R.) and JSPS (fellowship to
Y.Y.). Financial support for this work was provided by the NIH/
NIGMS (GM-073949), Bristol-Myers Squibb, and Sigma-
Aldrich.
(32) Wu, H.; Hynes, J. Org. Lett. 2010, 12, 1192.
D
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