Development of an asymmetric synthesis of a chiral quaternary FLAP inhibitor

Article abstract of DOI:10.1021/jo502550h

A practical sequence involving a noncryogenic stereospecific boronate rearrangement followed by a robust formylation with an in situ generated DCM anion has been developed for the asymmetric construction of an all-carbon quaternary stereogenic center of a FLAP inhibitor. The key boronate rearrangement was rendered noncryogenic and robust by using LDA as the base and instituting an in situ trapping of the unstable lithiated benzylic carbamate with the boronic ester. A similar strategy was implemented for the DCM formylation reaction. It was found that the 1,2-boronate rearrangement for the formylation reaction could be temperature-controlled, thus preventing overaddition of the DCM anion and rendering the process reproducible. The robust stereospecific boronate rearrangement and formylation were utilized for the practical asymmetric synthesis of a chiral quaternary FLAP inhibitor.

Full text of DOI:10.1021/jo502550h

Article
pubs.acs.org/joc
Development of an Asymmetric Synthesis of a Chiral Quaternary
FLAP Inhibitor
Keith R. Fandrick,* Jason A. Mulder,* Nitinchandra D. Patel, Joe Gao, Michael Konrad,‡
Elizabeth Archer,† Frederic G. Buono, Adil Duran,‡ Rolf Schmid,‡ Juergen Daeubler,‡
Jean-Nicolas Desrosiers, Xingzhong Zeng, Sonia Rodriguez, Shengli Ma, Bo Qu, Zhibin Li,
Daniel R. Fandrick, Nelu Grinberg, Heewon Lee, Todd Bosanac,† Hidenori Takahashi,† Zhidong Chen,†
Alessandra Bartolozzi,† Peter Nemoto,† Carl A. Busacca, Jinhua J. Song, Nathan K. Yee,
Paige E. Mahaney,† and Chris H. Senanayake
Department of Chemical Development, Boehringer-Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield,
Connecticut 06877-0368, United States
S
* Supporting Information
ABSTRACT: A practical sequence involving a noncryogenic
stereospecific boronate rearrangement followed by a robust
formylation with an in situ generated DCM anion has been
developed for the asymmetric construction of an all-carbon
quaternary stereogenic center of a FLAP inhibitor. The key
boronate rearrangement was rendered noncryogenic and robust
by using LDA as the base and instituting an in situ trapping of the
unstable lithiated benzylic carbamate with the boronic ester. A
similar strategy was implemented for the DCM formylation
reaction. It was found that the 1,2-boronate rearrangement for
the formylation reaction could be temperature-controlled, thus
preventing overaddition of the DCM anion and rendering the
process reproducible. The robust stereospecific boronate
rearrangement and formylation were utilized for the practical
asymmetric synthesis of a chiral quaternary FLAP inhibitor.
INTRODUCTION
■
Cardiovascular disease is a significant health issue and is expected
to become a greater public health threat with the aging
population;1 therefore, the development of effective new
treatments for atherosclerosis is required. Inhibitors of the
leukotriene (LT) biosynthesis pathway are effective treatments
for inflammatory-based diseases,2 and recently the LT pathway
Figure 1. Structure of FLAP inhibitor 1.
became the focus of atherosclerosis treatments. In particular, 5-
lipoxygenase-activating protein (FLAP) inhibitors have been
shown to affect biomarkers of atherosclerosis3 and reduce plaque
growth.4 Compound 15 (Figure 1) is under development as a
FLAP inhibitor while also sacrificing at least half of the overall
yield. As highlighted in a recent review article,8 the stereo-
FLAP inhibitor, and in order to continue the advancement of the
molecule in development, an efficient and reproducible synthesis
is required.
selective construction of all-carbon quaternary centers embed-
ded in acyclic systems has proved to be particularly challenging.
Compound 1 represents a significant challenge for develop-
Although there are several asymmetric methodologies for the
ment,6,7 as it contains diverse functionalities and at its core is an
synthesis of acyclic all-carbon stereocenters in the literature,9,10
all-carbon quaternary stereogenic center. Retrosynthetically the
these methods require cryogenic temperatures and/or have
target can be reduced to the chiral quaternary aryl aldehyde 5
(Scheme 1). A classical approach involves the construction of the
limited substrate scopes. Thus, the development of a new
practical synthesis is required.
benzylic quaternary center via ionization of the tertiary alcohol
followed by trapping with a suitable soft nucleophile.5a Due to
the formation of the benzylic carbocation the route is racemic
and a chiral separation is required to produce the enantiopure
Received: November 12, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/jo502550h
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 1. Retrosynthetic Strategy for 1
the planned Suzuki cross-coupling.14 In order to implement this
elegant methodology in the synthesis of the chiral quaternary
FLAP inhibitor 1, we needed to render the process practical for
large scale by eliminating the accumulation of the unstable
intermediates and also eliminating the required extreme
cryogenic temperatures. Herein we wish to report the develop-
ment of a practical and robust boronate rearrangement and
formylation process and its implementation in the practical
asymmetric synthesis of the FLAP inhibitor 1.
The required chiral secondary alcohol 11 was prepared by a
Noyori asymmetric transfer hydrogenation15 of bromoaceto-
phenone 10 (91% ee, Figure 3). Purging of the reaction with dry
nitrogen16 allowed the catalyst loading to be reduced to 0.1 mol
%. The crude intermediate alcohol 11 was treated with carbamyl
chloride to form the solid carbamate 12a, which after
crystallization increased the ee to 99.9%. The two-step synthesis
of carbamate 12a proceeded in 80% overall isolated yield and
99.9% ee.
RESULTS AND DISCUSSION
■
After evaluating several synthetic strategies for the construction
of the key all-carbon stereocenter, Aggarwal’s approach is
particularly attractive with respect to the availability of the key
starting materials and overall cost. Aggarwal and co-workers
reported a direct stereoretentive conversion of secondary
carbonates to tertiary boronates.11 Furthermore, the authors
demonstrated that the resulting boronic esters could then be
utilized as a handle for the introduction of a carbon unit to
complete the all-carbon quaternary stereocenter.12 This method-
ology offers an attractive synthetic strategy in which the
stereochemistry of the process is ultimately generated from a
well-known asymmetric reduction of a prochiral ketone (Figure
2).13 However, the two-step process required cryogenic
The reported Aggarwal boronate rearrangement process11,12 is
performed in three separate stages (Figure 4a); the first is the
deprotonation of the benzylic carbamate with an alkyllithium
base17 and then the trapping of the lithiated carbamate with the
boronic ester followed by a Lewis acid and/or thermally
promoted 1,2-alkyl rearrangement. This process was shown to
be quite general with regard to both the nature of the borane
substitution and the migratory group. However, due to the
accumulation of both the lithiated carbamate and the boronate
complex the process required cryogenic temperatures to
minimize racemization. However, if the deprotonation is
conducted in the presence of the boronic ester substrate, the in
situ formed lithiated carbamate would be quickly trapped by the
boronic ester to form the boronate complex (Figure 4b). This in
turn would bypass the accumulation of the configurationally
unstable lithiated carbamate and would allow the process to be
conducted at noncryogenic temperatures. In order to accomplish
the in situ deprotonation and render the process inherently
robust, a suitable base that is compatible with the electrophilic
boronic ester needed to be found.
Figure 2. Aggarwal’s approach for the construction of chiral quaternary
stereocenters from secondary chiral carbamates.
temperatures (−78 and −100 °C) due to the accumulation of
configurationally and thermally unstable intermediates. The
accumulation of these unstable intermediates precluded the use
of the process on a large scale, as these intermediates would be
formed and held for extended periods (1 h or more).
Furthermore, the use of alkyllithium bases prevented the use of
the more versatile aryl bromide substrates which was required for
Figure 3. Synthesis of chiral benzylic carbamate 12a.
B
DOI: 10.1021/jo502550h
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 4. Boronate rearrangement mechanisms.
Table 1. Initial Development of the LDA in Situ Deprotonation and Boronate Rearrangement
a
b
entry
R
base
solvent
temp (°C)
conversion (%)
ee erosion (%)
1
2
3
4
5
6
7
Cl (12a)
Br (12b)
Br (12b)
Br (12b)
Br (12b)
Br (12b)
Br (12b)
sec-BuLi (1.2 equiv)
Et2O
−30
−78
−30
−10
−25
−10
4
0
90
80
50
91
96
92
NA
−4
−4
−10
−0.8
LDA (2 M THF/Hept/EtPh)
LDA (2 M THF/Hept/EtPh)
LDA (2 M THF/Hept/EtPh)
LDA (1 M CpOMe
CpOMe
CpOMe
CpOMe
CpOMe
CpOMe
CpOMe
LDA (1 M CpOMe)
−1.0
−2.2
LDA (1 M CpOMe)
a
b
Molar conversion determined by HPLC analysis. Measured by ee erosion = (ee of product) − (ee of carbamate). Enantiomeric excess determined
by chiral HPLC analysis.
Table 2. Survey of Bases and Conditions for the in Situ DCM Anion Trapping
a
b
c
entry
base (amt (equiv))
amt of DCM (equiv)
solvent
addition time (min)
temp (°C)
conversion (%)
1
2
3
4
5
n-BuLi (3)
LDA (4)
LDA (4)
LDA (4)
LDA (4)
5
5
5
5
5
THF/CPME (4/1)
THF/CPME (4/1)
THF/CPME (4/1)
THF/CPME (4/1)
<1
<1
<1
<1
35
−30
−30
−10
0
85
90
90
93
THF/CPME (4/1)
−15
25
a
b
c
Base: n-BuLi 2.5 M in hexanes; LDA 2.0 M in THF/heptane/ethylbenzene. Addition time of the base to the DCM/boronate solution. Molar
conversion as determined by HPLC analysis.
Attempts to perform the in situ deprotonation of the benzylic
carbamate in the presence of the boronic ester with n-
butyllithium provided no observable product. As was suspected,
the alkyllithium base kinetically traps the boronic ester faster than
C
DOI: 10.1021/jo502550h
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
indicating that the deprotonation of DCM is faster than trapping
of the alkyllithium base with the boronic ester intermediate or the
competitive lithium halogen exchange. However, the reaction is
highly exothermic upon the addition of the alkyllithium base to
the reaction solution. The in situ deprotonation with LDA was
found to be far less exothermic and controllable by the rate of
LDA addition to the reaction. Our original investigation
suggested that the process required the use of a large excess of
DCM (6 equiv) and LDA (4 equiv) to drive the reaction to high
conversion (>80%). The reaction could be conducted at 0 °C
with a short LDA addition time (entry 4). However, this process
was found to be irreproducible, with wide variations of reaction
yields and byproduct formation. Therefore, we investigated the
long addition time of LDA, as this was suspected to be a defining
factor for the reaction irreproducibility. Indeed, the longer
addition times provided for significantly lower yields (20−40%,
−15 °C, entry 5) and the formation of several major byproducts.
We hypothesized that side reactions involved the overaddition of
DCM anion to product 20 due to the premature rearrangement
of intermediate 19 at higher reaction temperatures (Figure 5).
The boronate rearrangement of the DCM anion process was
monitored by ReactIR23 to determine the relative temperature at
which the 1,2-rearrangement of compound 19 to 20 occurs at an
appreciable rate to compete with the LDA addition time (Figure
6). After the boronate complex was formed at −45 °C, the system
was slowly warmed. At approximately −25 °C the rearrangement
was observed to form the chloromethylene insertion product 20.
Thus, when the reaction temperature is maintained below −45
°C, the premature boronate rearrangement to 20 can be
effectively suppressed and the borate complex is shielded from
overaddition of the DCM anion during the LDA addition. The
1,2-migration process was also studied computationally utilizing
density functional theory (DFT) with the B3LYP level of
theory24 and 6-311G basis set25 employing the Gaussian 09
software package26 (Figure 7). The 1,2-migration of the benzylic
fragment was found to be a smooth process with concurrent
displacement of the antiperiplanar chloride leaving group. The
calculated transition state was found to be 17.9 kcal/mol higher
Figure 5. Proposed mechanism and effects of temperature for the DCM
homologation.
it deprotonates the benzylic carbamate. However, the use of
LDA18 was found to be compatible with the boronic ester in the
in situ deprotonation and boronate formation (Table 1), as high
conversion and low ee erosion were obtained for the model
system.19,20 Furthermore, it was found that the reaction could be
conducted under noncryogenic conditions (4 °C) if coordinating
ethereal solvents (tetrahydrofuran) were removed from the
system (92% conversion and 97% ee, entry 7). It was
subsequently discovered that the use of methanolic magnesium
bromide was not needed, as the requisite tertiary boronic ester 8
was formed with this LDA process in near-perfect yield (99%,
Table 1) and with excellent stereoretention (98.6% ee) without
this additive.
To convert the optically enriched boronate 8 into chiral
aldehyde 17 containing the requisite all-carbon stereocenter, a
subsequent in situ deprotonation of DCM21 was implemented to
trap the highly unstable lithated DCM species upon its
formation.22 Initial attempts at the in situ deprotonation of
DCM at −30 °C with n-BuLi (2 M in hexanes) provided the
desired chloromethylene addition intermediate 20 (Table 2),
Figure 6. ReactIR monitoring of the LDA DCM formylation process.
D
DOI: 10.1021/jo502550h
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 7. Computational results for the 1,2-migration (B3LYP/6-311G).
Figure 8. Initial investigation of the NCS chlorination of oxime 22.
in energy from the corresponding dichloromethylene boronate
complex 19.
Table 3. Survey of Solvents for the in Situ DCM Anion
Formylation
Given this understanding of the stability of the DCM anion
and the key intermediate behavior with respect to temperature
and side product formation, we turned our attention to reducing
the amount of LDA in the process (Table 3) in order to render
the process efficient. The amount of LDA could be lowered to 1.5
equiv by using a more polar solvent system (4/1 THF/dioxane,
entry 3) to provide high conversions to the desired addition
product. The crude chloromethylene intermediate 20 was
subsequently oxidized in the same pot to the aldehyde 17 in
85−93% molar conversion. Oxime 22 (Figure 8) was formed
directly from the aldehyde in near-quantitative yield.
Attempts to use the crude oxime 22 in the subsequent N-
chlorosuccinimide oxidation27 and amido-oxime formation28 led
to significant decomposition. With purified oxime 22 the
chlorination reaction was found to require elevated temperatures
(Figure 8). Calorimetric monitoring of the reaction (Figure 8b)
found that the reaction had an unpredictable induction period,
which was found to be marked by a sharp exothermic event.
Furthermore, the crude oxime 22 from the formylation process
failed to thermally induce. It was suspected that the reaction is
a
amt of LDA
amt of DCM
(equiv)
conversion
b
entry
1
(equiv)
solvent
(%)
3.8
5
THF/CPME
(4/1)
94
2
3
2.0
1.5
3
2
THF
93
95
THF/1,4-dioxane
(4/1)
a
The base was added portionwise until the conversion was recorded as
>90% via HPLC analysis. Molar conversion as determined by HPLC
b
analysis.
autocatalytic with the formation of trace HCl29 during the
heating cycle. As the formylation of the tertiary boronic ester 8
does not reach complete conversion (>90%), trace amounts of
E
DOI: 10.1021/jo502550h
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 9. Formation of tertiary alcohol 24 from the incomplete formylation of boronic ester 8.
Figure 10. HCl-promoted chlorination of oxime 22.
boronic ester 8 would be converted to the tertiary alcohol 24
(Figure 9) during the hydrogen peroxide treatment. The trace
tertiary alcohol 24 could serve as an acid scavenger, thus
impeding the acid-promoted chlorination of the oxime. To test
this hypothesis, both crude and purified oxime 22 were treated
with NCS at 27−28 °C (Figure 10). HPLC and calorimetric
analysis indicated no reaction when the batch was held at this
temperature. However, upon the addition of catalytic HCl (37%
aqueous) an instant exothermic event that corresponded to the
formation of the chlorinated product by HPLC analysis was
observed. Furthermore, with the addition of catalytic amounts of
HCl at the onset of the reaction, the process was rendered
reproducible while eliminating the unpredictable exothermic
induction period and allowing the chemistry to be conducted at
ambient or subambient temperatures. The formylation process
was demonstrated with crude boronic ester 8, whereas a 90%
molar conversion was obtained for the intermediate aldehyde 17.
The crude aldehyde product (an oil) was directly processed to
the solid amido-oxime intermediate 23 in 99% ee and 52%
overall yield for the entire sequence from the boronic ester 8
(Figure 11).
Suzuki cross-coupling30 with the pinacol boronic ester 4
(Scheme 2). Although the cross-coupling could be performed
Scheme 2. Synthesis of 1 from Amido-Oxime 15
with Pd2(dba)3 and the tetrafluoroborate salt of P(t-Bu)3 (1 mol
% of Pd), it was found that the catalyst loading could be reduced
to 0.2 mol % (Pd) with the di-tert-butylphosphinoferrocene (t-
Bu2PFc-HBF4)31 ligand. The Suzuki product 2 was found to
precipitate directly from the reaction mixture in high yield and
purity. Following the synthesis of the oxadiazole32 from the CDI-
activated carboxylic acid 3, a final alkylation of the pyrazole
completed the synthesis. This sequence was employed to
produce multikilogram quantities of the target compound 1 to
support preclinical development.
With the key quaternary stereocenter established in >99% ee
as the amido-oxime 23, the substrate was in position for the
Figure 11. Synthesis of amido-oxime 23 from tertiary boronate 8.
F
DOI: 10.1021/jo502550h
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
to afford 141 g of a beige crystalline solid (12a). Yield: 84%, 99.7% ee.
1H NMR (CDCl3, 400 MHz): δ 7.46 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0
Hz, 2H), 5.78 (q, J = 7.0 Hz, 1H), 4.2−3.6 (m, 2H), 1.53−1.51 (d, J = 7.0
Hz, 3H), 1.4−1.1 (m, 12H). 13C NMR (CDCl3, 100 MHz): δ 154.8,
141.9, 131.5, 127.8, 121.2, 72.0, 46.3−45.3 (br), 22.6, 21.5−20.7 (br).
HRMS (TOF MS): [C15H22BrNO2 + H+] calculated 328.0907; found
328.0904.
CONCLUSION
■
In conclusion, a short and efficient asymmetric synthesis of a
structurally challenging FLAP inhibitor has been developed. The
asymmetric synthesis proceeded in nine steps and 35% overall
yield. The requirements for large-scale synthesis served as the
impetus for the development of a robust asymmetric synthesis of
the all-carbon quaternary carbon stereocenter of the target
molecule. By replacing sec-BuLi with LDA and instituting an in
situ trapping of the unstable lithiated carbamate, the key
boronate rearrangement was rendered noncyrogenic while the
substrate scope was also increased to include the requisite aryl
bromide substrate. Furthermore, a similar strategy was
implemented to convert the chiral tertiary boronate to the key
all-carbon quaternary aldehyde with excellent optical purity.
ReactIR and DFT molecular modeling studies were conducted to
study the key 1,2-migration process for the formylation reaction.
It was found that the 1,2-boronate rearrangement could be
temperature-controlled, thus preventing overaddition of the
DCM anion and rendering the reaction reproducible. We believe
that these new methods would provide the chemists with
valuable tools for the practical and stereoselective construction of
acyclic all-carbon quaternary chiral centers and the production of
complex bioactive compounds.
(S)-2-(1-(4-Bromophenyl)-1-cyclopropylethyl)-4,4,5,5-tetra-
methyl-1,3,2-dioxaborolane (8). In a dry, inert flask were placed (S)-
1-(4-bromophenyl)ethyl diisopropylcarbamate (12a; 100 g, 0.302 mol),
MTBE (600 mL), and cyclopropylboronic acid pinacol ester (9; 67.2
mL, 0.40 mol, 1.3 equiv) at 20 °C. The mixture was cooled to −15 °C. In
a second flask were placed diisopropylamine (38.15 g, 0.377 mol, 1.25
equiv) and MTBE (100 mL), and the mixture was cooled to 0 °C. n-
Butyllithium (2.5 M hexanes) (144.7 mL, 0.362 mol, 1.20 equiv) was
added over 30 min to the diisopropylamine solution, with the
temperature maintained at ∼0 °C. After it was stirred for 15 min at 0
°C, the LDA solution was added to the solution of carbamate/pinacol
ester, wih the temperature maintained below −10 °C. After complete
addition of the LDA solution, the mixture was warmed to +10 °C and
was stirred for 1 h. Upon completion the mixture was quenched by
addition of a solution of aqueous citric acid (20 g, 104 mmol in 380 mL
of water), with the temperature maintained below 30 °C. The bottom
layer was removed, and the organics were washed with water (400 mL)
and then concentrated by vacuum distillation (∼50 °C) to afford 8 as an
oily liquid: 295 g (31 wt %), 99% assay yield, 97.3% ee. The resulting
solution was used directly in the following step. 1H NMR (CDCl3, 500
MHz): δ 7.38 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 1.2−1.19 (d, J
= 5 Hz, 12H), 1.78 (s, 3H), 1.10−1.02 (m, 1H), 0.51−0.44 (m, 3H),
0.33−0.27 (m, 1H). 13C NMR (CDCl3, 125 MHz): δ 145.3, 128.7,
126.8, 116.7, 81.2, 65.4, 22.3, 22.3, 19.4, 16.4, 0.00, −0.70. HRMS (TOF
MS): [C17H24BBrO2 + H+] calculated 351.1125; found 351.1110.
(R)-2-(4-Bromophenyl)-2-cyclopropyl-N′-hydroxypropanimi-
damide (23). In a clean, dry flask were placed a solution of (S)-2-(1-(4-
bromophenyl)-1-cyclopropylethyl)-4,4,5,5-tetramethyl-1,3,2-dioxabor-
olane (8) in MTBE (50 g at 47 wt %, 68.2 mmol, 1.0 equiv) and
anhydrous THF (60 mL). The mixture was concentrated to remove
MTBE. The water content, as determined by Karl Fisher analysis, of the
resulting solution was targeted to be less than 350 ppm. If the water
content exceeded 350 ppm, iterative distillation was used to lower the
water content to the targeted level. To the mixture were added THF
(100 mL), 1,4-dioxane (25 mL), and dichloromethane (8.75 mL, 136.4
mmol, 2.0 equiv). The mixture was cooled to −50 °C, and lithium
diisopropylamide (2 M in THF/heptane/ethylbenzene; 51.2 mL, 102.3
mmol, 1.50 equiv) was added over a period of 30 min while the reaction
temperature was maintained at −50 to −45 °C and then held at −50 °C
for 16 h (overnight). After completion of the reaction (to α-
chloromethyl boronoester intermediate) was confirmed (monitored
by HPLC), methanol (24 mL) was added while the reaction
temperature was maintained below −20 °C. Following complete
addition, the mixture was warmed to ∼10 °C and was stirred for 20 min.
Afterward, aqueous hydrogen peroxide (30 wt %, 8.1 g, 71.6 mmol, 1.05
equiv) was added over a period of 30 min. After completion of the
reaction (aldehyde was confirmed by HPLC), 4 N aqueous hydrochloric
acid (37 wt %, 65 mL) and MTBE (25 mL) were added. The aqueous
phase was discarded, and the organics were washed with a 20 wt %
aqueous solution of sodium sulfite (30 mL). The organics were
concentrated, giving 49.7 g (31 wt %, 90% assay yield) of the crude
aldehyde 17. To an organic solution of (R)-2-(4-bromophenyl)-2-
cyclopropylpropanal (17) was added ethanol (60 mL), and the mixture
was concentrated to a volume of ∼45 mL. After further addition of
ethanol (60 mL) and cooling of the mixture to 10 °C, an aqueous
hydroxylamine hydrochloride solution (50 wt %, 6.28 mL, 102.3 mmol,
1.5 equiv) was added to the mixture, while the temperature was
maintained below 20 °C. The mixture was stirred at 20 °C for 3.5 h, and
then isopropyl acetate (141 mL) was added. The mixture was washed
with 5 wt % aqueous sodium chloride (2 × 59 mL) and concentrated to a
volume of ∼50 mL. To the concentrate was added acetonitrile (48 mL),
and the mixture was concentrated again to ∼50 mL. The material was
transferred from the flask, and acetonitrile (24 mL) was used to rinse the
EXPERIMENTAL SECTION
■
(S)-1-(4-Bromophenyl)ethyl Diisopropylcarbamate (12a). In a
Schlenk flask was placed dichloro(mesitylene)ruthenium(II) dimer
(307.5 mg, 0.5 mmol, 0.001 equiv) and (1S,2S)-N-p-Tosyl-1,2-
diphenylethylenediamine (748 mg, 2.0 mmol, 0.004 equiv). The
mixture was purged with argon three times, and degassed acetonitrile
(75 mL) followed by triethylamine (20 mL, 0.15 mol, 0.37 equiv) were
added to the flask. The mixture was stirred at 20 °C for 30 min. In a
separate flask was placed 1-(4-bromophenyl)ethan-1-one (10; 99%,
99.52 g, 0.5 mol, 1.00 equiv), the flask was purged with nitrogen three
times, and acetonitrile (375 mL) was added to the reactor, followed by
triethylamine (85 mL, 0.6 mol, 1.13 equiv) and formic acid (65 mL, 1.5
mol, 3.00 equiv) at 0−3 °C. After nitrogen sparging, the catalyst solution
was added and the mixture was stirred for 15 h with slow nitrogen
sparging. The mixture was concentrated to ∼30% volume, diluted with
ethyl acetate (150 mL), and then concentrated to ∼25% volume and
diluted again with ethyl acetate (700 mL). The organics were washed
with water (200 mL) and 5% aqueous sodium bicarbonate solution (200
mL). The organics were concentrated to a thick liquid via reduced
pressure (∼45 °C), acetonitrile (200 mL) was added, and the batch was
concentrated again to yield the crude product 11, which was used
directly in the next step.
In a 1 L 3-neck flask were placed diisopropylcarbamic chloride (94.1
g, 0.575 mol, 1.15 equiv), acetonitrile (400 mL), an acetonitrile solution
of (S)-1-(4-bromophenyl)ethan-1-ol (11), and finally triethylamine
(83.6 mL, 0.6 mol, 1.2 equiv). The mixture was heated at a mild reflux
(∼83 °C) for ∼15 h and was then concentrated via reduced pressure
(∼55 °C), and the concentrate was diluted with ethyl acetate (200 mL)
and reconcentrated to minimum volume (350 mL). At 20 °C ethyl
acetate (700 mL) was added and the organics were washed with water (2
× 200 mL). The organic layer was cut and passed through a pad of
Celite, and the flask and pad were rinsed with ethyl acetate (50 mL). The
combined filtrates were concentrated via reduced pressure (∼50 °C).
Methanol (200 mL) was added, and the mixture was concentrated.
Methanol (270 mL) was added, and the mixture was cooled to −5 °C,
seeded, and stirred at ∼0 °C for 1 h, after which an off-white slurry was
formed. A precooled (∼0 °C) solution of methanol−water (960 mL)
was added to the slurry over 2 h while the reaction temperature was kept
between −5 and 0 °C, then the slurry was held at −5 °C for 12 h. The
product was collected by filtration and was rinsed with a precooled (0
°C) 1:1 mixture of methanol and water (150 mL). The solids were dried
on the filter and then under vacuum with no heating (the melting point
of the product carbamate is 39−40 °C) for 20 h with a nitrogen stream
G
DOI: 10.1021/jo502550h
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
flask; the rinse was combined with the product and concentrated under
reduced pressure to provide 21.6 g of crude 22 (74.4 wt %; 98.2% assay
yield for oxime step, 88% combined yield for two steps). HRMS (TOF
MS) for compound 22: [C12H14BrNO + H+]: calculated 268.0332;
found 268.0339. The concentrate was used in the next step directly. The
solution of (R)-2-(4-bromophenyl)-2-cyclopropylpropanal oxime (22)
in acetonitrile from the previous step was cooled to 15 °C, and aqueous
hydrochloric acid (37 wt %, 1.93 mL, 22.2 mmol, 0.2 equiv) was added.
A solution of N-chlorosuccinimide (18.1 g, 132.9 mmol, 1.2 equiv) in
acetonitrile (110 mL) was then added while the temperature was
maintained at ∼15 °C. The resulting mixture was stirred at this
temperature for 5 h. After reaction completion (chlorinated oxime
intermediate) was confirmed (monitored by HPLC), the mixture was
cooled to 0 °C and aqueous ammonia (28−30 wt %, 29.7 mL, 221.5
mmol, 2.0 equiv) was added while the reaction temperature was
maintained at <20 °C. The mixture was warmed to ∼20 °C and stirred
for 3.5 h. The mixture was cooled to ∼10 °C, and 11.5 M HCl (65 mL)
and water (75 mL) were added slowly to maintain the temperature
between 20 and 25 °C. Heptane (100 mL) and MTBE (50 mL) were
added to the mixture. The top layer (heptane/MTBE) was removed,
and the bottom layer (ACN/water/product) was retained. To this
product layer were added isopropyl acetate (195 mL) and 4 N aqueous
sodium hydroxide (169 mL). After mixing and settling, the bottom
aqueous layer was removed and the top organic layer was washed with
water (75 mL). The final organic layer was concentrated to ∼50 mL
volume, and 2-propanol (250 mL) was added. The mixture was
concentrated to remove 250 mL of solvents to reach a final volume of 50
mL. Heptane (25 mL) was added, and the mixture was heated to ∼55
°C, cooled to ∼48 °C, seeded, and then cooled to 30 °C over 2 h.
Heptane (120 mL) was then added to the mixture over 2 h. The mixture
was concentrated at 30 °C under reduced pressure to reach a batch
volume of ∼90 mL, and then the resulting slurry was further cooled to to
−3 °C over 2 h and stirred for an additional 1 h at −3 °C. The product
was collected by filtration, and the solid was rinsed with a cold mixture of
1:4 IPA−heptane (20 mL) and air-dried for 2 h, followed by vacuum
drying at 50 °C for 12 h, to afford 23.51 g of 23 as an off-white solid (75%
yield for the amidoxime step, 99.1% ee). 1H NMR (CDCl3, 500 MHz): δ
8.89 (s, 1H), 7.45 (d, J = 8.5, 2H), 7.32 (d, J = 8.5, 2H), 4.39 (s, 1H),
1.37−1.32 (m, 1H), 1.31 (s, 3H), 0.60−0.49 (m, 2H), 0.38−0.33 (m,
1H), 0.30−0.26 (m, 1H). 13C NMR (CDCl3, 125 MHz): δ 155.6, 141.3,
129.2, 127.1, 118.9, 43.8, 20.0, 16.7, 0.00, −0.92. HRMS (TOF MS):
[C12H15BrN2O + H+] calculated 283.0441; found 283.0441.
5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-
amine (4). In a clean, dry, nitrogen-inerted flask (#1) were placed 2-
amino-5-bromopyrimidine (30 g, 172 mmol, 1.0 equiv), bis-
(pinacolato)diboron (48.16 g, 190 mmol, 1.1 equiv), di-tert-
butylphosphinoferrocene tetrafluoroborate (0.144 g, 0.35 mmol, 0.2
mol %), tris(dibenzylidineacetone)palladium (0.158 g, 0.17 mmol, 0.1
mol %), and potassium acetate (33.84 g, 345 mmol, 2.0 equiv). Flask #1
was evacuated and purged with nitrogen. In flask #2, 2-methyltetrahy-
drofuran (120 mL) was sparged with nitrogen and then placed in flask
#1. The mixture was heated to 82 °C over 0.5 h and then held at 82 °C
for 4.5 h (a slurry forms). The mixture was cooled to ∼60 °C
(suspension), and tetrahydrofuran (390 mL) was added to make a
solution. The solution was filtered at 60 °C to remove solids, ensuring
both filter and the receiver were heated to 60 °C. Tetrahydrofuran (150
mL) heated to 60 °C was used to rinse the flask and filtered solids. The
combined filtrates were distilled at ∼55 °C under vacuum to the
minimum stirrable volume. Ethanol (150 mL) was added, and the
mixture was again concentrated to minimum volume. Ethanol (390 mL)
was added, and the mixture was heated to 65 °C and held for 1 h. The
ethanol solution was then filtered through a heated (65 °C) filter
containing CUNO type 5 carbon. The reactor and filter were rinsed with
preheated (60 °C) ethanol (60 mL). The combined filtrates were placed
in a clean flask and were concentrated at 60 °C under vacuum. The
resulting slurry was cooled to 20 °C over 2 h and then held at 20 °C for 2
h. The solids were collected by filtration and were rinsed with ethanol
(90 mL). The solid was dried on the funnel for 1 h and then in a vacuum
oven at 45 °C for 8 h, giving 28.4 g of 4 as a white crystalline solid (75%
yield, 97.8 wt %, Pd 2 ppm). Mp: 212 °C. 1H NMR (CDCl3, 500 MHz):
δ 8.59 (s, 1H), 5.69 (s, 2H), 1.33 (s, 12H). 13C NMR (CDCl3, 125
MHz): δ 164.9, 164.4, 84.1, 25.0. HRMS (TOF MS): [C10H16BN3O2 +
H+] calculated 222.1408; found 222.1399.
(R,Z)-2-(4-(2-Aminopyrimidin-5-yl)phenyl)-2-cyclopropyl-N′-
hydroxypropanimidamide (2). In a clean, dry, nitrogen-inerted flask
were placed 23 (50 g, 170 mmol, 1.0 equiv), 4 (49.5 g, 222 mmol, 1.3
equiv), FcPtBu2HBF4 (0.162 g, 0.22 mol %), and Pd(OCOCF3)2 (0.117
g, 0.20 mol %). The flask was evacuated and purged with nitrogen. A
solution of potassium phosphate hydrate (78 g, 341 mmol, 2 equiv) in
water (200 mL) was placed in the flask, followed by isopropyl alcohol
(250 mL) (both liquids were previously sparged with nitrogen). The
mixture was heated to 80 °C over 0.5 h with good agitation (biphasic
mixture) and then held at 80 °C for 4 h. A solution of N-acetyl-L-cysteine
(7.0 g) in water (300 mL) was added at a constant rate over 1 h, at a
temperature of 80 °C. The slurry was held at 80 °C for 4 h, cooled to 20
°C over 4 h, and then held at 20 °C for 30 min. The solids were collected
by filtration and were rinsed with water (150 mL) followed by isopropyl
acetate (150 mL). The product was dried on the filter at 20 °C for 1 h
and then in a vacuum oven at 40 °C for 30 h, giving 50.5 g of 2 as an off-
white crystalline solid (95% yield, 99.7% ee, Pd 180 ppm). Mp: 201 °C.
1H NMR (DMSO-d6, 500 MHz): δ 9.18 (s, 1H), 8.55 (s, 2H), 7.55 (d, J
= 8.48 Hz, 2H), 7.43 (d, J = 8.48 Hz, 2H), 6.73 (s, 2H), 5.06 (s, 2H), 1.50
(m, 1H), 1.11 (s, 3H), 0.51 (m, 1H), 0.33−0.42 (m, 2H),), 0.20 (m,
1H). 13C NMR (DMSO-d6, 125 MHz): δ 162.9, 157.1, 155.8, 145.4,
133.1, 127.6, 124.8, 122.1, 45.1, 21.2, 18.4, 2.2, 0.9. HRMS (TOF MS):
[C16H19N5O + H+] calculated 298.1662, found 298.1651.
(R)-5-(4-(1-(5-(1H-Pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)-1-
cyclopropylethyl)phenyl)pyrimidin-2-amine (27). In a clean, dry,
nitrogen-inerted flask were placed carbonydimidazole (CDI) (35.4 g,
218 mmol, 1.2 equiv) and tetrahydrofuran (378 mL). To the CDI slurry
was added a solution of 1H-pyrazole-4-carboxylic acid (3; 26.5 g, 236
mmol, 1.3 equiv) in dimethylformamide (135 mL) slowly at 20 °C, and
the flask was rinsed with tetrahydrofuran (60 mL) into the CDI solution.
The mixture was heated to 50 °C over 0.5 h and held at 50 °C for 0.5 h
(gas evolution was observed). A slurry of 2 (60.0 g, 90.0 wt %, 182 mmol,
1 equiv) in THF (358 mL) was added to the activated acid, and the
mixture was heated to 105 °C (removing the THF by distillation) and
then held at 105 °C for 17 h. The mixture was cooled to 20 °C over 1 h,
and then ethyl acetate (757 mL) and water (378 mL) were added. The
layers were separated, and the organic layer was washed with water (378
mL). The organic layers were then heated to 50 °C and passed through a
filter containing CUNO type 3 carbon. The filter was rinsed with ethyl
acetate (216 mL), and the combined filtrates were added to a clean flask
(no Pd) and were concentrated under vacuum at 55−60 °C to 150−200
mL total volume. At 55−60 °C the solution was seeded and stirred for
0.5 h. At 55−60 °C isopropyl acetate (324 mL) was added and the slurry
was concentrated to 150−200 mL total volume. Heptane (108 mL) was
added at 55−60 °C, and the slurry was stirred at 57 °C for 1 h and then
cooled to 20 °C over 4 h and held at 20 °C for 8 h. The product was
collected by filtration, and the solids were rinsed with isopropyl acetate
(54 mL) and then heptane (162 mL). The solids were dried on the
funnel for 1 h at 20 °C and then for 24 h at 60 °C under vacuum, yielding
58.9 g of 27 as an off-white crystalline solid (85.9% yield, 99.7% ee, Pd
<2 ppm). Mp: 190 °C. 1H NMR (DMSO-d6, 500 MHz): δ 8.54 (s, 2H),
8.19 (s, 1H), 7.56 (d, J = 8.71 Hz, 2H), 7.37 (d, J = 8.71 Hz, 2H), 6.75 (s,
2H), 1.67 (m, 1H), 0.64 (m, 1H), 0.31−0.51 (m, 3H). 13C NMR
(DMSO-d6, 125 MHz): δ 175.7, 170.8, 162.9, 155.9, 143.8, 133.6, 127.4,
125.2, 121.8, 106.1, 42.8, 22.0, 19.4, 2.1, 1.1. HRMS (TOF MS):
[C20H19N7O + H+] calculated 374.1724; found 374.1721.
(R)-2-(4-(3-(1-(4-(2-Aminopyrimidin-5-yl)phenyl)-1-cyclopro-
pylethyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)-N,N-dimethy-
lacetamide (1). In a clean, dry, nitrogen-inerted flask were placed 27
(50.0 g, 99.1 wt %, 132.7 mmol, 1.0 equiv), DMF (150 mL), and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU; 27.8 mL, 185.8 mmol, 1.4
equiv). To the mixture was added 2-chloro-N,N-dimethylacetamide
(28; 17.74 mL, 172.5 mmol, 1.3 equiv) over 10 min with cooling to
maintain an internal temperature of <50 °C. The mixture was heated to
50 °C and held for 1 h. At 50 °C isopropyl acetate (200 mL) was added,
and the solution was seeded at 52 °C. Water (150 mL) was added at 52
°C slowly over 1 h, and the slurry was agitated at this temperature for 0.5
H
DOI: 10.1021/jo502550h
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
h (creates initial seed bed). Water (150 mL) was added to the flask at 52
°C slowly over 1 h, and the slurry was agitated at this temperature for 1 h.
Water (300 mL) was added to the reaction mixture at 52 °C slowly over
1 h, the mixture was agitated at 52 °C for 2 h, and the slurry was cooled
to 20 °C linearly over 4 h and stirred at 20 °C for 9 h. The product was
collected by filtration, and the solid was rinsed consecutively with water
(150 mL), isopropyl acetate (150 mL), and heptane (150 mL). The
solid was dried for 1 h at 20 °C on the funnel and then for 24 h at 55 °C
under vacuum, giving 58.3 g of 1 as an off-white crystalline solid (94.4%
yield, 98.5 wt %, 99.8% ee). Crude 1 could be further purified by
recrystallization from ethanol/water. Mp: 196 °C. 1H NMR (DMSO-d6,
500 MHz): δ 8.55 (s, 2H), 8.49 (s, 1H), 8.06 (s, 1H), 7.56 (d, J = 8.48
Hz, 2H), 7.38 (d, J = 8.48 Hz, 2H), 6.75 (s, 2H), 5.22 (s, 2H), 3.03 (s,
3H), 2.85 (s, 3H), 1.67 (m, 1H), 0.64 (m, 1H), 0.31−0.52 (m, 3H). 13C
NMR (DMSO-d6, 125 MHz): δ 175.7, 170.4, 165.9, 162.9, 155.9, 143.8,
138.6, 134.0, 133.6, 127.4, 125.2, 121.8, 106.7, 53.2, 42.8, 35.90, 35.3,
22.1, 19.4, 2.1, 1.1. HRMS (TOF MS): [C24H26N8O2 + H+] calculated
459.2251, found 459.2241.
Applications of Transition Metal Catalysis in Drug Discovery and
Development: An Industrial Perspective; Crawley, M. L., Trost, B. M.,
Eds.; Wiley: Hoboken, NJ, 2012.
(7) (a) Anderson, N. G. Practical Process Research & Development;
Academic Press: San Diego, CA, 2000; p 354. (b) Practical Process
Development: Current Chemical and Engineering Challenges; Blacker, J.;
Williams, M. T., Eds.; RSC Publishing: London, 2011; p 374.
(8) Marek, Y. M.; Pasco, M.; Mejuch, T.; Gilboa, N.; Chechik, H.; Das,
J. P. J. Am. Chem. Soc. 2014, 136, 2682.
(9) (a) Wu, J.; Mampreian, D. M.; Hoveyda, A. H. J. Am. Chem. Soc.
2005, 127, 4584−4585. (b) Lee, K.-s.; Brown, M. K.; Hird, A. W.;
Hoveyda, A. H. J. Am. Chem. Soc. 2006, 128, 7182−7184. (c) Martin, D.;
Kehrli, S.; d’Augustin, M.; Clavier, H.; Mauduit, M.; Alexakis, A. J. Am.
Chem. Soc. 2006, 128, 8416−8417. (d) Fillion, E.; Wilsily, A. J. Am.
Chem. Soc. 2006, 128, 2774−2775. (e) Wilsily, A.; Fillion, E. Org. Lett.
2008, 10, 2801−2804. (f) Wilsily, A.; Lou, T.; Fillion, E. Synthesis 2009,
12, 2066−2082. (g) Wilsily, A.; Fillion, E. J. Org. Chem. 2009, 74, 8583−
8594.
(10) (a) Hrdina, R.; Muller, C. E.; Wende, R. C.; Lippert, K. M.;
̈
ASSOCIATED CONTENT
■
Benassi, M.; Spengler, B.; Schreiner, P. R. J. Am. Chem. Soc. 2011, 133,
7624−7627. (b) Kimura, T.; Yamamoto, N.; Suzuki, Y.; Kawano, K.;
Norimine, Y.; Ito, K.; Nagato, S.; Iimura, Y.; Yonaga, M. J. Org. Chem.
2002, 67, 6228−6231. (c) Wang, Z.-X.; Tu, Y.; Frohn, M.; Zhang, J.-R.;
Shi, Y. J. Am. Chem. Soc. 1997, 119, 11224−11235.
(11) (a) Stymiest, J. L.; Bagutski, V.; French, R. M.; Aggarwal, V. K.
Nature 2008, 456, 778−782. (b) Bagutski, V.; Ros, A.; Aggarwal, V. K.
Tetrahedron 2009, 65, 9956−9960. (c) Bagutski, V.; French, R. M.;
Aggarwal, V. K. Angew. Chem., Int. Ed. 2010, 49, 5142−5145.
(d) Sonawane, R. P.; Jheengut, V.; Rabalakos, C.; Larouche-Gauthier,
R.; Scott, H. K.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2011, 50, 3760−
3763.
S
* Supporting Information
Figures, tables, and a CIF file giving crystallographic data for
1
compound 23, H NMR, 13C NMR, and chiral HPLC spectra,
and computational data. This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail for K.R.F.: keith.fandrick@boehringer-ingelheim.com.
*E-mail for J.A.M.: jason.mulder@boehringer-ingelheim.com.
■
(12) (a) Rangaishenvi, M. V.; Singaram, B.; Brown, H. C. J. Org. Chem.
1991, 56, 3286−3294. (b) Scott, H. K.; Aggarwal, V. K. Chem. Eur. J.
2011, 17, 13124−13132.
Present Addresses
†Department of Medicinal Chemistry, Boehringer-Ingelheim
Pharmaceuticals Inc., 900 Ridgebury Road, P.O. Box 368,
Ridgefield, CT 06877-0368, United States.
(13) Farina, V.; Reeves, J. T.; Senanayake, C. H.; Song, J. J. Chem. Rev.
2006, 106, 2734−2793.
‡Department of Chemical Development, Boehringer-Ingelheim
Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397
Biberach/Riß, Germany.
(14) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457−2483.
(b) Stanforth, S. P. Tetrahedron 1998, 54, 263−303. (c) Kotha, S.;
Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633−9695. (d) Bellina,
F.; Carpita, A.; Rossi, R. Synthesis 2004, 14, 2419−2440.
(15) (a) Fujii, A.; Hashiguchi, S.; Uematsu, N.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 2521−2522. (b) Noyori, R.; Hashiguchi, S.
Acc. Chem. Res. 1997, 30, 97−102.
(16) Blacker, J. A.; Thompson, P. Scale-up Studies in Asymmetric
Transfer Hydrogenation. In Asymmetric Catalysis on Industrial Scale, 2nd
ed.; Blaser, H.-U., Schmidt, E., Eds.; Wiley: Hoboken, NJ, 2010; pp
265−290.
(17) (a) Hoppe, D.; Hintze, F.; Tebben, P. Angew. Chem., Int. Ed. Engl.
1990, 29, 1422−1424. (b) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed.
Engl. 1997, 36, 2282−2316.
(18) Matteson, D. S.; Soundararajan, R.; Ho, O. C.; Gatzweiler, W.
Organometallics 1996, 15, 152−163.
(19) Fandrick, K. R.; Patel, N. D.; Mulder, J. A.; Gao, J.; Konrad, M.;
Archer, E.; Buono, F. G.; Duran, A.; Schmid, R.; Daeubler, J.; Fandrick,
D. R.; Ma, S.; Grinberg, N.; Lee, H.; Busacca, C. A.; Song, J.; Yee, N. K.;
Senanayake, C. H. Org. Lett. 2014, 16, 4360−4364.
(20) For general purpose large-scale reactors the minimum preferred
operational internal temperature is 0 to −40 °C.
(21) Matteson, D. S.; Man, H.-W.; Ho, O. C. J. Am. Chem. Soc. 1996,
118, 4560−4566.
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) Bonow, R. O.; Smaha, L. A.; Smith, S. C., Jr.; Mensah, G. A.;
Lenfant, C. Circulation 2002, 106, 1602−1605.
(2) Stock, N. S.; Bain, G.; Zunic, J.; Li, Y.; Ziff, J.; Roppe, J.; Santini, A.;
Darlington, J.; Prodanovich, P.; King, C. D.; Baccei, C.; Lee, C.; Rong,
H.; Chapman, C.; Broadhead, A.; Lorrain, D.; Correa, L.; Hutchinson, J.
H.; Evans, J. F.; Prasit, P. J. Med. Chem. Lett. 2011, 54, 8013−8029.
(3) Hakonarson, H.; Thorvaldsson, S.; Helgadottir, A.; Gudbjartsson,
D.; Zink, F.; Andresdottir, M.; Manolescu, A.; Arnar, D. O.; Andersen,
K.; Sigurdsson, A.; Thorgeirsson, G.; Jonsson, A.; Agnarsson, U.;
Bjornsdottir, H.; Gottskalksson, G.; Einarsson, A.; Gudmundsdottir, H.;
Adalsteinsdottir, A.; Gudmundsson, K.; Kristjansson, K.; Hardarson, T.;
Kristinsson, A.; Topol, E. J.; Gulcher, J.; Kong, A.; Gurney, M.;
Thorgeirsson, G.; Stefansson, K. J. Am. Med. Assoc. 2005, 293, 2245−
2256.
(4) Tardif, J.-C.; L’Allier, P. L.; Ibrahim, R.; Gregoire, J. C.; Nozza, A.;
́
Cossette, M.; Kouz, S.; Lavoie, M.-A.; Paquin, J.; Brotz, T. M.; Taub, R.;
Pressacco, J. Cir. Cardiovasc. Imaging 2010, 3, 298−307.
(5) (a) Bartolozzi, A.; Bosanac, T.; Chen. Z.; De Lombaert, S.; Huber,
J.; Lo, H. Y.; Loke, P. L.; Weimin, L.; Morwick, T. M.; Olague, A.;
Riether, D.; Tye, H.; Wu, L.; Zindell, R. (Boehringer Ingelheim
International GMBH) WO 2012/024150 A1, 2012. (b) Fandrick, K. R.;
Gao, J. J.; Mulder, J. A.; Patel, N.; Zeng, X. (Boehringer Ingelheim
International GMBH) WO 2013/119751 A1, 2013.
(22) (a) Matteson, D. S.; Soundararajan, R.; Ho, O. C.; Gatzweiler, W.
Organometallics 1996, 15, 152−163. (b) During the scaling of the DCM
homologation, a similar process was reported: Pulis, A. P.; Aggarwal, V.
K. J. Am. Chem. Soc. 2012, 134, 7570−7574.
(23) For selected examples of ReactIR used in process development,
see: (a) Grabarnick, M.; Zamir, S. Org. Process Res. Dev. 2003, 7, 237−
243. (b) Connolly, T. J.; Matchett, M.; McGarry, P.; Sukhtankar, S.;
Zhu, J. Org. Process Res. Dev. 2006, 10, 391−397.
(6) Busacca, C. A.; Fandrick, D. R.; Song, J. J.; Senanayake, C. H.
Transition Metal Catalysis in the Pharmaceutical Industry. In
I
DOI: 10.1021/jo502550h
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(24) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648−5652. (b) Lee, C.;
Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785−789.
(25) (a) Krishnan, R.; Binkley, J. S.; Seeger, R.; Pople, J. A. J. Chem.
Phys. 1980, 72, 650−654. (b) McLean, A. D.; Chandler, G. S. J. Chem.
Phys. 1980, 72, 5639−5648.
(26) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.;
Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.;
Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich,
̈
S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.;
Fox, D. J. Gaussian 09, Revision D.01; Gaussian, Inc., Wallingford, CT,
2009.
(27) Liu, K.-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45,
3916−3918.
(28) Menzel, K.; Machrouhi, F.; Bodenstein, M.; Alorati, A.; Cowden,
C.; Gibson, A. W.; Bishop, B.; Ikemoto, N.; Nelson, T. D.; Kress, M. H.;
Frantz, D. E. Org. Process Res. Dev. 2009, 13, 519−524.
(29) Hansen, E. C.; Levent, M.; Connolly, T. J. Org. Process Res. Dev.
2010, 14, 574−578.
(30) (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979,
20, 3437−3440. (b) Miyaura, N.; Suzuki, A. Chem. Commun. 1979,
No. 19, 866−867. (c) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95 (7),
2457−2483.
(31) (a) Busacca, C. B.; Eriksson, M. C.; Haddad, N.; Han, Z. S.;
Lorenz, J. C.; Qu, B.; Zeng, X.; Senanayake, C. H. Org. Synth. 2013, 90,
316−326. (b) Mann, G.; Incarvito, C.; Rheingold, A. L.; Hartwig, J. F. J.
Am. Chem. Soc. 1999, 121, 3224−3225. (c) Qu, B.; Haddad, N.; Han, Z.
S.; Rodriguez, S.; Lorenz, J. C.; Grinberg, N.; Lee, H.; Busacca, C. A.;
Krishnamurthy, D. K.; Senanayake, C. H. Tetrahedron Lett. 2009, 50,
6126−6129.
(32) Kayukova, L. A. Pharm. Chem. J. 2005, 39, 539−547.
J
DOI: 10.1021/jo502550h
J. Org. Chem. XXXX, XXX, XXX−XXX