Study of Sustainability and Scalability in the CpRh(III)-Catalyzed Direct C-H Amidation with 1,4,2-Dioxazol-5-ones

Article abstract of DOI:10.1021/acs.oprd.5b00164

The practical aspects of CpRh(III)-catalyzed direct C-H amidation with 1,4,2-dioxazol-5-ones were investigated on the operational safety, use of green solvent, and scalability. Differential scanning calorimeter (DSC) measurement showed that 3-phenyl-1,4,2

Full text of DOI:10.1021/acs.oprd.5b00164

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Study of Sustainability and Scalability in the
Cp*Rh(III)ꢀCatalyzed Direct C−H Amidation with
1,4,2ꢀDioxazolꢀ5ꢀones
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Yoonsu Park,†,‡ Soyeon Jee,†,‡ Jeung Gon Kim,*,‡,† and Sukbok Chang*,‡,†
†Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST),
Daejeon, 305ꢀ701, Republic of Korea
‡ Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS),
Daejeon, 305ꢀ701, Republic of Korea
AUTHOR INFORMATION
Corresponding Author
* Jeung Gon Kim jeunggonkim@kaist.ac.kr
* Sukbok Chang sbchang@kaist.ac.kr
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Table of Contents
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ABSTRACT
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The practical aspects of Cp*Rh(III)ꢀcatalyzed direct C−H amidation with 1,4,2ꢀdioxazolꢀ5ꢀones
were investigated on the operational safety, use of green solvent, and scalability. Differential
scanning calorimeter (DSC) measurement showed that 3ꢀphenylꢀ1,4,2ꢀdioxazolꢀ5ꢀone is
thermally stable while benzoyl azide, a conventionally employed precursor of acyl nitrene,
rapidly decomposes to isocyanate. It was confirmed that the replacement of acyl azide with
1,4,2ꢀdioxazolꢀ5ꢀone brings not only high reactivity but also improvement in safety. In respect to
a green process development, functional group tolerant Cp*Rh(III) catalyst exhibited high
reactivity in ethyl acetate, successfully replacing 1,2ꢀdichloroethane solvent used in the original
report. Upon the validation on safety and environmental concerns, scalability was also tested.
Two different types of arenes bearing pyridyl and oxime directing groups showed excellent
conversions on tens of gram scale reactions, and single recrystallization gave desired products
with high yields and purity.
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Keywords
C−H Amidation, Rhodium(III) catalysis, 1,4,2ꢀDioxazolꢀ5ꢀone, Solvent, Safety, Scalability
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Introduction
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Direct C−H amination is one of the most important themes in C−H functionalization which has
been studied intensively by many research teams, eventually replacing conventional approaches
utilizing alkenyl or aryl (pseudo)halides.1,2 Our group has also participated in the development of
highly efficient and environmentally benign catalytic C−H amination reactions.3 During the
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search of robust catalytic systems, we recently disclosed Cp*Rh(III)ꢀcatalyzed C−H amidation
with 1,4,2ꢀdioxazolꢀ5ꢀones, which possesses attractive features such as low catalyst loading,
mild conditions, broad scope of substrates with high functional group tolerance, no requirement
of external oxidants, and release of carbon dioxide as a single byproduct (Scheme 1).4
Scheme 1. Robust Cp*Rh(III)ꢀCatalyzed C−H amidation with 1,4,2ꢀdioxazolꢀ5ꢀone
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Scheme 2. Mechanistic Proposal of Rh(III)ꢀCatalyzed C−H Amidation with 1,4,2ꢀDioxazolꢀ5ꢀ
one
Our mechanistic investigation on the Cp*Rh(III)ꢀmediated C−H amidation process unveiled
that competitive binding of the rhodium metal center to an amidating reagent or substrate is
closely related to the reaction efficiency (Scheme 2).3a−c,4 An amino precursor with strong
coordination affinity would facilitate the formation of a metallacycle intermediate 3 bound to an
amidating reagent over the resting state 2. A group of dioxazolone derivatives were found to
have 103 to 108 times higher coordination propensity than organic azides. Among those
dioxazolones, 1,4,2ꢀdioxazolꢀ5ꢀone exhibited especially excellent efficiency on the imido
insertion process, thus leading to a robust catalytic C−H amidation system. In addition to the
observed high reactivity, 1,4,2ꢀdioxazolꢀ5ꢀones were found to be more convenient for the
preparation, storage, and use when compared to the corresponding acyl azides.
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To obtain an additional feature of this C−H amidation protocol, we decided to scrutinize the
practical aspect of the originally optimized reaction conditions. When a reaction goes to a large
scale production, many factors should be considered and adjusted mainly due to the critical
issues of reproducibility, safety, environmental effect, cost, and so on.5 Described herein is our
investigations on the safety, environmental parameters including solvent, and scalability
(Scheme 3).
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Scheme 3. Practical Aspects of Cp*Rh(III)ꢀCatalyzed C−H Amidation with 1,4,2ꢀDioxazolꢀ5ꢀ
ones
Results and Discussions
Safer Amidating Reagent - Acyl Azide versus 1,4,2-Dioxazol-5-one. Acyl azides have been
known as a facile carbon donor to furnish an amide group upon the Curtius rearrangement to the
corresponding isocyanates.6 For the utilization of acyl azides as a nitrogen donor in the acyl
amino group transfer, our group recently developed two complementary catalytic systems of
Ir(III) and Ru(II), which have opened a new synthetic opportunity of acyl azides in organic
synthesis.3a,d,e However, their fast rearrangement to isocyanates still leaves a concern on the
selectivity and safety in the use of acyl azides.3e In particular, the safety issue related to an
explosiveness of azide compounds always hampers large scale applications.7 In this context,
dioxazolones have drawn attention as safe alternatives to acyl azides.8 Research teams of Sanofi9
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and Pfizer10 demonstrated the process applicability of dioxazolones as an intermediate for the
isocyanate formation (Lossen rearrangement).11 Given that acyl nitrene is a common
intermediate obtained from both acyl azide and dioxazolone, several examples were reported for
the use of dioxazolones as an acyl nitrene source including our recent development of highly
reactive Cp*Rh(III)ꢀmediated C−H amidation (Scheme 4).4,12
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Scheme 4. NꢀAcyl Nitrene Formation from Acyl Azides or 1,4,2ꢀDioxazolꢀ5ꢀones
Recently, the research team of Sanofi briefly described the excellent thermal stability of
dioxazolones over azides during the process development of Lossen rearrangement on a
kilogram scale.9 To gain detailed information, we conducted differential scanning calorimeter
(DSC) measurements of benzoyl azide (7) and 3ꢀphenylꢀ1,4,2ꢀdioxazolꢀ5ꢀone (8). In the
temperature range of ꢀ20 ~ 100 oC, crystallization temperature (Tc) and melting temperature (Tm)
were observed during the first and second cycle of benzoyl azide treatment (Figure 1a). There
was an abrupt decrease in intensity of both Tc and Tm peaks on the second cycle. This result can
be attributed to the thermal degradation of benzoyl azide to isocyanate upon heating so that the
amount of benzoyl azide is decreased accordingly. In the third cycle, no peaks of benzoyl azide
were observed, again confirming the complete decomposition. In a stark contrast, when 3ꢀ
phenylꢀ1,4,2ꢀdioxazolꢀ5ꢀone was subjected to the same conditions, both Tc and Tm curves did not
show any noticeable degradation over three cycles (Figure 1b). The melting enthalpy of
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dioxazolone 8 remained almost similar after stabilization (93.2 J/g on 2nd cycle and 91.3 J/g on
3rd cycle, Table 1), which indicates the good thermal stability compared to benzoyl azide. In our
previous protocol of the Rhꢀcatalyzed amidation by using 3ꢀphenylꢀ1,4,2ꢀdioxazolꢀ5ꢀone,4 CO2
was found to be released only by the action of Rh(III) catalyst so that the uncontrolled selfꢀ
decomposition is not expected to occur under the optimized experimental conditions. However,
we would like to emphasize that several classes of 1,4,2ꢀdioxazolꢀ5ꢀones, for example 3ꢀ
fluroroalkyl ones, are known to detonate under relatively mild conditions, thus still special
caution should be applied on the dioxazolone handling.12a
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Figure 1. DSC Measurement of (a) Benzoyl azide 7 and (b) 3ꢀPhenylꢀ1,4,2ꢀdioxazolꢀ5ꢀone 8
Table 1. Melting and Crystallization Enthalpies of 3ꢀPhenylꢀ1,4,2ꢀdioxazolꢀ5ꢀonea
ΔH (J/g)
Crystallization
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a
Each value was obtained from the integral of crystallization and melting peak on DSC
measurement. See the Supporting information for details.
Solvent Study. In our previously reported procedures on the direct C−H amidation, most
reactions employed 1,2ꢀdichloroethane as a solvent,3.4 which has also been found to be highly
efficient in numerous examples of other types of C−H functionalizations as well (Scheme 1).
Upon the awareness of its undesirable side effects to environment, 1,2ꢀdichloroethane is mostly
banned in industrial applications.13 Therefore, we envisaged that the replacement of 1,2ꢀ
dichloroethane by greener solvents would increase the value of our amidation protocols.
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In this context, a list of organic solvents were examined in the Cp*Rh(III)ꢀmediated C−H
amidation with 3ꢀphenylꢀ1,4,2ꢀdioxazolꢀ5ꢀone (8, Table 2). Two different substrates bearing
pyridine and ketoxime directing groups were applied to validate the generality of this amidation
reaction. With a 2.0 mol % catalyst loading, protic solvents such as alcohols and acids showed
good efficiency with 2ꢀphenylpyridine (6), but low conversion was observed with ketoximeꢀ
containing arene (9, entries 2−4). Acetonitrile was ineffective for both substrates presumably due
to the strong affinity of solvent to the metal center, thus blocking imido complex formation
(entry 5). A series of polar aprotic solvents gave good conversion overall (entries 6−10).
Delightfully, excellent reactivity was observed in ethyl acetate, a desirable green solvent for the
process chemistry. The use of ethyl acetate as a reaction solvent is not a general option because
of reactive ester functionality. We believe that excellent functional group tolerance and mild
reaction conditions of the present Cp*Rh(III) catalytic system make it possible to accommodate
ethyl acetate as a reaction medium.4
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Table 2. Solvent Study in the C−H Amidation of two Substrates with 3ꢀPhenylꢀ1,4,2ꢀdioxazolꢀ5ꢀ
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Yield (%)b
Entry
Solvent
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Methanol
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Acetic Acid
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Acetonitrile
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Acetone
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Dimethylformamide
Ethyl Acetate
Tetrahydrofuran
1,2ꢀDimethoxyethane
Toluene
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Substrate (0.20 mmol) and 8 (0.22 mmol). NMR yields (internal standard:
1,1,2,2ꢀtetrachloroethane).
We also examined a similar solvent screening in the preparation of 1,4,2ꢀdioxazolꢀ5ꢀones to
accommodate the guidelines.13 The replacement of solvent to ethyl acetate from dichloromethane
turned out to be successfully adaptable in a reaction between carbonyldiimidazole and
benzohydroxamic acid (Scheme 5), thus the complete elimination of chlorinate solvents could be
realized both in the preparation of amidating reagents and in the key C−H amidation reaction.
Scheme 5. Synthesis of 3ꢀPhenylꢀ1,4,2ꢀdioxazolꢀ5ꢀone
Scale-up Study. We previously demonstrated the scalability in a gram scale C−H amidation (5
mmol) of 2ꢀphenylpyridine with 3ꢀphenylꢀ1,4,2ꢀdioxazolꢀ5ꢀone using a 0.50 mol % catalyst
loading using 1,2ꢀdichloroethane as a solvent.4 Since we found that the greener solvent ethyl
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acetate could replace 1,2ꢀdichloroethane in a subꢀmmol reaction, its applicability even on a large
scale was next examined. Pleasingly, the same level of reactivity was observed in a large scale
reaction (Scheme 6). At first, the synthesis of 1,4,2ꢀdioxazolꢀ5ꢀone was carried out at a 100
mmol scale (Scheme 5). The addition of 1,1ꢀcarbonyldiimidazole (CDI) to a suspension of
benzohydroxamic acid in ethyl acetate gave a complete conversion within 1 h. Extraction of the
crude reaction mixture with aqueous 1 N HCl solution (250 mL, 2.5 equiv) removed imidazole
almost completely. The crude mixture after the removal of ethyl acetate was dissolved in toluene,
and then filtration of undissolved impurities followed by evaporation of toluene gave the desired
product in 72% yield (11.8 g). The Rh(III)ꢀcatalyzed C−H amidation was subsequently
conducted (Scheme 6). To the solution of 3ꢀphenylꢀ1,4,2ꢀdioxazoleꢀ5ꢀone 8 (210 mmol, 1.05
equiv), [Cp*RhCl2]2 (0.500 mol %, 1.00 mmol), and AgNTf2 (2.00 mol %, 4.00 mmol) in ethyl
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acetate (120 mL) at 40 C, 2ꢀphenylpyridine 6 (200 mmol, 1.00 equiv) was added over 3.5 h
o
using a syringe pump, maintaining the reaction temperature under 45 C.14 Since the C−H
amidation was found to be highly exothermic (ꢀ290 kJ/mol),15 a careful control of reaction rate
was required to prevent uncontrollable heat and CO2 emission. When 2ꢀphenylpyridine was
added at once, a surge of heat and CO2 emission was observed. The resulting temperature
elevation caused further rate amplification, thus a loss of control was witnessed.16 The amidation
1
was completed in 4 h checked by H NMR monitoring. Insoluble silver salt was removed by
filtration. The crude mixture obtained after evaporation of ethyl acetate was recrystallized in 2ꢀ
butanol (200 mL) at room temperature to give 43.2 g product 10 (79% yield), and its purity was
determined to be >99% by HPLC analysis.
The same procedure was also applied to a substrate 12 bearing a ketoxime directing group (50.0
mmol scale, Scheme 6b). Although the reaction required slightly higher temperature (60 oC), the
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desired amidation product 13 was obtained in good yields (51% with 0.500 mol % catalyst and
64% with 1.00 mol % catalyst) by following the same purification procedure as that of 10.
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Scheme 6. Large Scale C−H Amidations using Cp*Rh(III) Catalyst with 1,4,2ꢀDioxazolꢀ5ꢀone
Conclusions
In conclusion, we examined the practical aspects in the Cp*Rh(III)ꢀcatalyzed C−H amidation
with 1,4,2ꢀdioxazolone. Several key guidelines for the potential process chemistry were
successfully checked: good thermal stability of the present amidating reagent, the use of nonꢀ
chlorinated solvents (ethyl acetate herein), nonꢀtoxic byproducts (CO2 only), mild conditions (40
o
~ 60 C), no need of special equipment to maintain inert atmosphere, convenience in handling
reagents, and easy purification procedure of products. Under these satisfactory prerequisites, the
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direct C−H amidation was readily conducted up to tens of gram scale without difficulty to afford
the desired amidated products in high yields. Since the reaction is also featured by broad
substrate scope and excellent functional group tolerance, we anticipate the use of this highly
sustainable and efficient C−N bond formation method in process chemistry in the near future.
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Experimental Section
General Methods. All commercial reagents and solvents (HPLC or reagent grade) were used as
received. Analytical thin layer chromatography (TLC) was performed on preꢀcoated silica gel 60
F
254 plates. Visualization on TLC was achieved by UV light (254 nm). 1H NMR was recorded on
Agilent Technologies DD2 (600 MHz). Chemical shifts were quoted in parts per million (ppm)
referenced to the residual solvent peak (CHCl3) or 0.0 ppm for tetramethylsilane. The following
abbreviations were used to describe peak splitting patterns when appropriate: s = singlet, d =
doublet, m = multiplet. Coupling constants, J, were reported in hertz (Hz). 13C NMR was
obtained on Agilent Technologies DD2 (150 MHz) and was fully decoupled by broad band
proton decoupling. Chemical shifts were reported in ppm referenced to the residual solvent
(CHCl3) peak. Infrared (IR) spectra were acquired on Bruker Alpha ATR FTꢀIR Spectrometer.
Frequencies are given in wave numbers (cmꢀ1) and only selected peaks were reported. High
resolution mass spectrum was obtained from the KAIST Research Analysis Center by using ESI
method. DSC scans were recorded on TA Instruments DSC Q20. Purity of compounds were
examined using Shimadzu Prominence HPLC system composed of LCꢀ20A pump, SPDꢀM20A
photoꢀdiode array detector, and Shimꢀpack prepꢀODS(H) column (4.6 mm X 250 mm) with
acetonitrile as an eluent at the flow rate of 1.0 mL/min. Reaction enthalpy was measured on
Omnical SuperCRC calorimeter.17 Reaction temperature and pressure were recorded using
Vernier LabQuest system.
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General procedure for the solvent study (Table 2). To an ovenꢀdried screw capped vial with a
spinvane triangularꢀshaped Teflon stirbar were added 2ꢀphenylpyridine or 1ꢀphenylethanꢀ1ꢀone
Oꢀmethyl oxime (0.20 mmol), 3ꢀphenylꢀ1,4,2ꢀdioxazolꢀ5ꢀone (36 mg, 0.22 mmol), [Cp*RhCl2]2
(2.4 mg, 2.0 mol %), AgNTf2 (6.2 mg, 8.0 mol %), and solvent (0.5 mL) under atmospheric
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conditions. The reaction mixture was stirred in a heating block at 40 C for 18 h. The reaction
was cooled to room temperature, filtered through a pad of Celite and then washed with CH2Cl2
(20 mL). The solvent was removed under reduced pressure and yield was measured by 1H NMR
spectroscopy using 1,1,2,2ꢀtetrachloroethane (34 mg, 0.20 mmol) as an internal standard.
Measurement of reaction enthalpy. A vial (21 x 70 mm) equipped with a magnetic stir bar and
a teflon septa cap was charged with [Cp*RhCl2]2 (15.5 mg, 0.0250 mmol), AgNTf2 (38.8 mg,
0.100 mmol), 3ꢀphenylꢀ1,4,2ꢀdioxazolꢀ5ꢀone (856 mg, 5.25 mmol), and ethyl acetate (3 mL)
[Sample Vial]. The other vial was prepared identically except the addition of [Cp*RhCl2]2 and
AgNTf2 [Reference Vial]. Both vials were placed in a calorimeter which was preheated at 40 oC.
Two gas tight syringes with 2ꢀphenylpyridine (776 mg, 5.00 mmol) were placed in syringe ports.
Once thermal equilibrium was achieved, 2ꢀphenylpyridine in each port was rapidly injected at
the same time. All injection ports were plugged with cotton wool for insulation. Strong heat
emission was detected from the sample vial. The reaction was allowed to run until no heat
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transfer was observed. The vials were removed and H NMR analyses showed full conversion
(>98%) of the sample vial and no conversion or degradation of the reference vial. The integration
of the observed heat flow vs. time curves using WinꢀCRC software gave a value of ꢀ 1450 J for 5
mmol scale, which is equal to ꢀ 290 kJ / mol.
Synthesis of 3-phenyl-1,4,2-dioxazol-5-one (8) (100 mmol Scale). An ovenꢀdried 300 mL
roundꢀbottom flask was equipped with a magnetic stir bar. Benzohydroxamic acid (13.7 g, 100
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mmol), ethyl acetate (200 mL), and 1,1’ꢀcarbonyldiimidazole (16.3 g, 101 mmol) were added
sequentially under atmospheric conditions. After vigorous stirring for 1 h, the reaction mixture
was quenched with 1 N HCl (250 mL, 2.5 equiv), and extracted with ethyl acetate (200 mL). The
separated organic layer was dried over MgSO4 (12 g) and the solvent was removed under
reduced pressure. The crude product was reꢀdissolved in toluene (200 mL) and filtered through a
pad of Celite. The solvent was evaporated under reduced pressure to afford the desired product
as a white solid (11.8 g, 72%).
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Synthesis of 1-(4-bromophenyl)ethan-1-one O-methyl oxime (12) (100 mmol Scale). A
roundꢀbottom flask (500 mL) equipped with magnetic stir bar and reflux condenser was charged
with a solution of 4’ꢀbromoacetophenone (19.9 g, 100 mmol) in methanol (100 mL) and H2O
(250 mL). NaOAc (32.8 g, 400 mmol) and methoxyamine hydrochloride (39.1 g, 468 mmol)
were added in oneꢀportion under atmospheric condition. The resulting mixture was stirred in a
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preꢀheated oil bath at 80 C for 12 h. The reaction mixture was cooled to room temperature and
extracted with ethyl acetate (200 mL x 2). The combined organic layer was washed with
saturated aqueous NaHCO3 (200 mL) and dried over MgSO4 (12 g). The solvent was removed
under reduced pressure to afford the desired product as a light yellow oil (22.6 g, 99% yield).
Synthesis of N-[2-(pyridin-2-yl)phenyl]benzamide (10) (200 mmol Scale). To an ovenꢀdried
250 mL threeꢀneck roundꢀbottom flask equipped with a magnetic stir bar were added 3ꢀphenylꢀ
1,4,2ꢀdioxazolꢀ5ꢀone (34.24 g, 210 mmol), [Cp*RhCl2]2 (620 mg, 1.00 mmol), and AgNTf2
(1.55 g, 4.00 mmol) under atmospheric condition. After the addition of ethyl acetate (120 mL),
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the flask was placed on the preheated oil bath of 40 C. Sensors were installed to monitor the
pressure and temperature of reaction mixture and temperature of heating bath. 2ꢀPhenylpyridine
(31.0 g, 200 mmol) was added using a syringe pump over 3.5 h while maintaining the reaction
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temperature under 45 C (see the Supporting information for a temperature log). With a
placement of needle of 22 gauge as a CO2 outlet, no sign of pressure accumulation was detected.
The completion of amidation was confirmed at 4 h by 1H NMR. White precipitation was formed
during cooling down to room temperature, ethyl acetate (400 mL) was added to dissolve the
precipitate. The reaction mixture was filtered through a Celite pad to remove undissolved silver
salts and washed with ethyl acetate (30 mL). The solvent was removed under reduced pressure
and resulting solid was recrystallized in 2ꢀbutanol (200 mL) at ambient temperature for 12 h. The
resulting precipitate was filtered and washed with 2ꢀbutanol (120 mL) to afford the desired
product as a white solid (43.2 g, 79% yield, > 99% purity by HPLC analysis at 254 and 280 nm).
Synthesis of N-{5-bromo-2-[1-(methoxyimino)ethyl]phenyl}benzamide (13) (50 mmol
Scale). To an oven dried 250 mL roundꢀbottom flask equipped with a magnetic stir bar were
added 3ꢀphenylꢀ1,4,2ꢀdioxazolꢀ5ꢀone (8.56 g, 52.5 mmol), [Cp*RhCl2]2 (155 mg, 0.250 mmol)
and AgNTf2 (388 mg, 1.00 mmol) under atmospheric condition. After the addition of ethyl
acetate (30 mL) and 1ꢀ(4ꢀbromophenyl)ethanꢀ1ꢀone Oꢀmethyl oxime (11.4 g, 50.0 mmol), the
flask was capped with septum and equipped with empty balloon to mediate the pressure of
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liberated CO2. The resulting mixture was stirred in a preꢀheated oil bath at 60 C for 18 h. The
reaction was cooled to room temperature and precipitation was formed. After dissolving the
precipitate with the additional ethyl acetate (100 mL), the resulting solution was filtered through
a Celite pad and washed with ethyl acetate (50 mL). The solvent was removed under reduced
pressure and the resulting solid was dissolved in 2ꢀbutanol (50 mL) for recrystallization at
ambient temperature for 12 h. The resulting precipitate was filtered and washed with 2ꢀbutanol
(25 mL) to afford the desired product as a pale yellow solid (8.77 g, 51% yield, > 99% purity by
HPLC analysis at 254 and 280 nm). The same procedure with [Cp*RhCl2]2 (310 mg, 0.500
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mmol) and AgNTf2 (776 mg, 2.00 mmol) gave the product of 11.1 g (64% yield, > 99% purity
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by HPLC analysis at 254 and 280 nm). mp 125 − 127 C; H NMR (600 MHz, CDCl3) δ 11.79
(s, 1H), 9.04 (s, 1H), 7.96 (d, J = 7.7 Hz, 2H), 7.58 – 7.52 (m, 1H), 7.51 – 7.45 (m, 2H), 7.35 (d,
J = 1.5 Hz, 1H), 7.30 – 7.22 (m, 1H), 4.01 (s, 3H), 2.30 (s, 3H); 13C NMR (150 MHz, CDCl3) δ
166.3, 157.1, 138.5, 135.6, 132.1, 129.8, 128.7 (2C), 127.6, 126.3 (2C), 124.2, 124.0, 121.7,
62.5, 13.9; IR (cmꢀ1) 3104, 3066, 3031, 2958, 1675, 1598, 1566, 1522, 1398, 1282, 1046, 698;
HRMS (ESI) m/z calcd. for C16H15BrN2O [M+Na]+: 369.0215, found: 369.0229.
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ASSOCIATED CONTENT
Supporting Information. Copies of DSC data, heat transfer measurement, reaction temperature
log, NMR spectra, and HPLC chromatograms. This material is available free of charge via the
Internet at http:// pubs.acs.org.
ACKNOWLEDGMENT
We thank Heejun Hwang (KAIST & SK biopharmaceuticals) for valuable discussions and
Joonsoo Chun (KAIST) for the assistance of DSC measurement. Y.P. is a recipient of
Kwanjeong Educational Foundation scholarship. This research was supported by the Institute for
Basic Science (IBSꢀR010ꢀD1) in Korea.
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14) Temperature logs are available in the Supporting information.
15) The heat of reaction was obtained from integration of heat flow vs. time data using a
calorimeter. See the Supporting information for details.
16) In case of a large scale (200 mmol), heat alleviation was not efficient with a system of flask
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and oil bath. Reaction temperature was raised to reflux (82 C) in 15 min. See the Supporting
information for details.
17) Mathew, S. P.; Iwamura, H.; Blackmond, D. G. Angew. Chem., Int. Ed. 2004, 43, 3317.
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