Exploiting the differential reactivities of halogen atoms: Development of a scalable route to IKK2 inhibitor AZD3264

Article abstract of DOI:10.1021/op500105n

An efficient and scalable synthesis of AZD3264 is described in which the differential reactivities of various halogen atoms have been employed. The process involves five linear chemical steps with three isolated stages starting from commercially available fragments.

Full text of DOI:10.1021/op500105n

Article
pubs.acs.org/OPRD
Exploiting the Differential Reactivities of Halogen Atoms:
Development of a Scalable Route to IKK2 Inhibitor AZD3264
Andiappan Murugan,* Sreekanth Bachu, Sulur G. Manjunatha, Ravi Ramakrishnan,
Vasantha Krishna Kadambar, Chandrasekhara Reddy, Venkata Rao Torlikonda, Sajan George,
Sridharan Ramasubramanian, and Sudhir Nambiar
Pharmaceutical Development, AstraZeneca India Pvt. Ltd, Hebbal, Off Bellary Road, Bangalore 560024, India
S
* Supporting Information
ABSTRACT: An efficient and scalable synthesis of AZD3264 is described in which the differential reactivities of various halogen
atoms have been employed. The process involves five linear chemical steps with three isolated stages starting from commercially
available fragments.
Evaluating New Synthetic Approaches. The API 1
could be disconnected into four simpler molecular fragments
that could be assembled in a suitable sequence to access the
title compound as shown in Figure 2.
INTRODUCTION
■
Inhibition of IkB-kinase IKK2 has been identified as one of the
novel pathways to treat inflammatory conditions such as
asthma, chronic pulmonary obstructive disorder (COPD) and
rheumatoid arthritis.1 AZD3264 (1 in Figure 1) is a small
molecule inhibitor of IKK2 currently in preclinical development
for the potential treatment of COPD and asthma.
The disconnection provided the three commercially available
fragments 3, 6, and 9 (which were also used in the MedChem
synthesis), which are to be regioselectively reacted with a
suitably substituted central aromatic ring. To select such a
suitably substituted aromatic ring, we envisaged to exploit the
differential reactivities of the different halogen atoms and
accordingly had three different commercially available halo-
aromatic substrates as starting materials as shown in Figure 3.
The plan was to introduce the pyrrolidinol fragment using
the relatively noncomplicated base-promoted nucleophilic
substitution of fluorine with N-boc-pyrrolidinol at C1. It was
important to sequence the introduction of bromothiophene
system at C2 and isoxazole system at C5, for which we made
use of the reactivity differences between chlorine, bromine and
iodine substituents on the aromatic system.
Figure 1.
Evaluation of New Route 1. The new route to 1 (Scheme
2) was designed to start from 1-bromo-4-chloro-2-fluoroben-
zene (10). The aromatic nucleophilic substitution reaction with
N-Boc-3-pyrrolidinol (3) in 2-MeTHF using potassium tert-
butoxide gave the bromo intermediate 13 in near quantitative
yield. The borylation of 13 via halogen metal exchange with n-
hexLi followed by quenching with triisopropyl borate and acidic
work-up yielded boronic acid 14. The Suzuki reaction of 14
with bromothiophene 6 proceeded smoothly using Pd-118
catalyst and potassium carbonate as base in DMF as solvent.
The chloro intermediate 15 was precipitated by the addition of
water. The next challenge was to carry out the Suzuki reaction
of 15 with isoxazole boronate 9. Although there are several
efficient Pd catalytic systems reported in the literature to
activate the chloro substituent towards Suzuki reactions,3 this
substrate 15 failed to give the Suzuki product 16 in acceptable
yields. After a thorough catalytic screen, we have identified a
catalytic system (Neolyst CX21 iPr catalyst, NaOH as base in
The medicinal chemistry synthesis of 1 is presented in
Scheme 1. The synthesis began with the aromatic nucleophilic
substitution reaction of 2-fluorobromobenzene (2) with (S)-N-
Boc-3-pyrrolidinol 3 to give the bromo intermediate 4, which
was borylated via halogen metal exchange using n-hexLi in THF
followed by treatment with triisopropyl borate and acidic work-
up to give the boronic acid intermediate 5. Suzuki coupling of
the boronic acid 5 with bromothiophene 62 afforded the
intermediate 7. Intermediate 7 was subjected to regioselective
bromination using bromine in acetic acid. This reaction was
nonregioselective and yielded 17% of the required isomer 8.
The bromo compound 8 was coupled with isoxazole boronate
ester 9 by another Suzuki reaction to get the title compound.
The overall yield of the synthesis was <6%. Moreover, the last
step involved Pd-catalyzed Suzuki reaction; the product, having
a free secondary amine function, posed significant challenge in
scavenging residual palladium from the API (active pharma-
ceutical ingredient). Though this route was suitable to deliver
gram quantities of API for early development, it was
undesirable for large multikilogram scale manufacture to
support the clinical development.
Received: March 27, 2014
Published: April 29, 2014
© 2014 American Chemical Society
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Scheme 1. MedChem route to AZD3264
Figure 2.
Figure 3.
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Scheme 2
Scheme 3
Scheme 4
DMAc solvent) that gave a maximum conversion of 54%. This
conversion was unsatisfactory for a practical synthesis, and
hence this route was dropped.
Evaluation of Route 2: From 1,4-Dibromo-2-fluoro-
benzene. This route (Scheme 3) was designed to obtain the
desired regioselectivity by utilizing the stereoelectronic differ-
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Scheme 5
ences between the two bromo substituents. The fluoro
displacement of 11 with 3 worked well using KOtBu in 2-
MeTHF. The next challenge was to introduce the isoxazole
function at C5 by regioselective Suzuki reaction. We predicted
that the steric hindrance offered by the pyrrolinol ether
function at C1 should differentiate the bromine functions at C2
and C5 (carbons are numbered with reference to Figure 1)
towards Suzuki reaction, and also the electron-donating nature
of the ether function would further enhance the regioselectivity.
Accordingly the Suzuki reaction of 17 with boronate ester 9
was performed using the relatively weaker catalyst Pd-101 in
the presence of triethylamine and water in 2-MeTHF. Although
the perceived concept of the regioselection was proved to be
correct, the maximum selectivity towards the required product
18 was 82% (by HPLC area %) along with 8% of regioisomer
19 and 10% of bis-coupled product 20. The other catalytic
systems did not offer any better selectivity. The separation of
these impurities was found to be challenging, and hence this
route was also dropped.
Evaluation of Route 3: From 1-Iodo-4-bromo-2-
fluorobenzene. To enhance the regioselectivity of the Suzuki
reaction on 17, we replaced the 5-bromo function with an iodo
function (Scheme 4). Accordingly, we began the synthesis with
the iodo compound 12. The fluoro displacement worked well
using the standard protocol to give the iodo-bromo
intermediate 21. The Suzuki reaction of 21 with isoxazole
boronate ester 9 using Pd-101 in 2-MeTHF gave more than
98% selectivity and 100% conversion. The product 22 was
isolated as a solid by the addition of n-heptane as anti-solvent.
The bromo intermediate 22 could be borylated in two ways:
(i) halogen metal exchange with n-hexLi followed by quenching
with triisopropyl borate and acidic work-up yielded boronic
acid 23. The boronic acid 23 reacted smoothly with
bromothiophene 6 in the presence of Pd-118 catalyst in 2-
MeTHF to give N-Boc-protected API 16. (ii) Miyaura
borylation of 22 with bis-pincolatodiboran using Pd-106 in
DMF yielded boronate ester 24 (Scheme 5); 24 reacted with 6
under similar reaction conditions as those of 23.
isoxazole 9 using Pd-101 catalyst and aqueous sodium
carbonate as base. The reaction worked well with >98%
regioselectivity. After the usual aqueous work-up, the
intermediate 22 was precipitated by the addition of n-heptane
to the organic phase. The isolated yield stood at 80% over 2
steps.
The halogen metal exchange on 22 with n-hexLi required
cryogenic conditions. The optimized reaction condition
required a controlled addition of n-hexLi to a mixture of 22
and tris-isopropylborate in THF at −78 °C. The isolation of the
boronic acid 23 seemed to be challenging due to its instability,
and hence telescoping was seen as a better option. After
quenching of the above reaction mixture with dilute HCl, the
boronic acid intermediate was extracted in 2-MeTHF and
subjected to Suzuki coupling with bromothiophene 6 using Pd-
118 as catalyst and aqueous potassium carbonate as base. The
N-Boc-protected API 16 precipitated out during the course of
the reaction and was isolated by simple filtration in 78% yield
over two steps.
The other important challenge was the removal of residual
palladium. We felt that the intermediate 16 in its nitrogen-
protected state would offer better solubility and would also
have less affinity towards Pd. After abbreviated solvent and
scavenger screens, 2-butanone was selected as solvent and
Quadrasil MP (from Johnson Matthey) was selected as solid
scavenger, which reduced the residual palladium to <50 ppm as
desired. Finally the N-Boc deprotection was performed using
HCl in a 2-propanol/water system, and the API 1 was isolated
by basification with aqueous ammonia.
CONCLUSIONS
■
A highly efficient and scalable synthesis of AZD3264 from
readily available building blocks has been developed. We made
use of the difference in the reactivities of halogen atoms to
devise a regioselective synthesis of the title compound.
EXPERIMENTAL DETAILS
■
General. All reactions were performed under a nitrogen
atmosphere unless otherwise specified. Water is distilled water.
All reagents and solvents were obtained from commercial
suppliers and were used without any further purification.
1H NMR and 13C NMR spectra were acquired on a 400
MHz instrument. NMR spectra were recorded on Bruker
spectrometers operating at the specified proton frequencies in
DMSO-d6 solution with tetramethylsilane (TMS) as internal
reference. LC−MS spectra were obtained using an Agilent 1200
series LC instrument and LC/MSD SL detector with +ve
atmospheric pressure electrospray ionization (APESI).
However, the Miyaura borylation was found to be
inconsistent and sensitive to the catalyst quality. Moreover,
our efforts to develop one-pot borylation4 and Suzuki reaction
also failed to yield the desired results.
Route Decision and Process Development. Route 3
(Scheme 4) appeared to be superior to all other routes. Hence
it was decided to develop this route for the large scale synthesis.
The first step reaction of fluoro compound 12 with 3 in the
presence of potassium tert-butoxide in 2-MeTHF was fairly
straightforward and provided a clean reaction. However, the
intermediate 21 is a gummy mass that is difficult to isolate.
Since the reaction profile was clean, this was telescoped to the
next stage. The 2-MeTHF solution of 21 was reacted with the
tert-Butyl (3S)-3-[2-Bromo-5-(3,5-dimethylisoxazol-4-
yl)phenoxy]pyrrolidine-1-carboxylate (22). To a stirred
suspension of potassium tert-butoxide (1.71 kg, 15.10 mol) and
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1
tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (3) (2.52 kg,
12.78 mol) in 2-MeTHF (52.44 L) was added 1-bromo-2-
fluoro-4-iodobenzene (20) (3.56 kg, 11.62 mol) at ambient
temperature. The resultant mixture was heated to 70−75 °C
and maintained at that temperature under stirring until
complete conversion was confirmed by HPLC. The reaction
mixture was cooled to 25 °C and quenched with water (17.48
L). The aqueous layer was discarded. To the organic layer was
charged sodium carbonate (5.57 kg, 52.28 mol) and water
(31.45 L). After degassing with nitrogen, to the resultant
reaction mass were added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)isoxazole (9) (2.93 kg, 12.78 mol) and
tetrakis(triphenylphosphine)palladium (Pd-101) (0.67 kg, 0.58
mol), and the mixture was heated to 50 °C for 15 h and then 70
°C for 5 h. The reaction completion was confirmed by HPLC.
The reaction mixture was cooled to 25 °C and concentrated
under reduced pressure, and the product was crystallized by
addition of n-heptane (34.96 L) and isolated by filtration. This
product was formed as a mixture of rotamers. 1H NMR
(DMSO-d6, 400 MHz): δ 1.38−1.41 (br, 9H), 2.08−2.15 (m,
2H), 2.24 (s, 3H), 2.42 (s, 3H), 3.35−3.57 (m, 4H), 5.18 (s,
1H), 6.93 (d, 1H, J = 8 Hz), 7.15 (s, 1H), 7.66 (d, 1H, J = 8
Hz). 13C NMR (DMSO-d6, 100.6 MHz): δ 10.35, 11.30, 28.10,
30.09, 30.90 (rotamer), 43.68, 43.94 (rotamer), 50.93, 51.17
(rotamer), 76.88, 77.76 (rotamer), 78.47, 111.45, 115.22,
115.86, 123.01, 130.76, 133.46, 153.52, 158.06, 165.43. DEPT
NMR (DMSO-d6, 100.6 MHz): δ 10.36, 11.30, 28.08, 30.09,
30.90 (rotamer), 43.68, 43.94 (rotamer), 50.93, 51.17
(rotamer), 76.86, 77.75 (rotamer), 115.84, 123.00, 133.46.
HRMS calcd for C20H26BrN2O4 (M + H)+: 437.1070, found
yield. This product was formed as a mixture of rotamers. H
NMR (DMSO-d6, 400 MHz): δ 1.34 (s, 9H), 2.23−2.28 (m,
5H), 2.45 (s, 3H), 3.38−3.62 (m, 4H), 5.22 (s, 1H), 6.89−6.94
(m, 1H), 7.04−7.08 (m, 2H), 7.3 (br, 1H), 7.70−7.75 (m, 2H),
7.83 (s, 1H), 10.95 (s, 1H). 13C NMR (DMSO-d6, 100.6
MHz): δ 10.49, 11.40, 28.02, 30.39, 31.21 (rotamers), 43.84,
44.13 (rotamers), 50.61, 50.99 (rotamers), 76.34, 77.20
(rotamers), 78.38, 111.77, 114.10, 114.34, 115.61, 122.00,
125.12, 127.19, 128.94, 150.33, 152.03, 153.72, 154.37, 158.19,
165.22, 167.02. DEPT NMR (DMSO-d6, 100.6 MHz): δ 10.51,
11.41, 28.01, 30.39, 31.21 (rotamers), 43.85, 44.14 (rotamers),
50.60, 50.98 (rotamers), 76.33, 77.18 (rotamers), 114.06,
114.32 (rotamers), 120.88, 121.70, 121.80 (rotamers), 127.14.
HRMS calcd for C26H31N5NaO6S (M + Na)+: 564.1893, found
564.1844. [α]25 +44.20 (c 0.5, DMSO).
D
AZD3264 (1). A stirred solution of tert-butyl (3S)-3-[2-(4-
carbamoyl-5-methyl-2-thienyl)-5-(3,5-dimethylisoxazol-4-yl)-
phenoxy]pyrrolidine-1-carboxylate (16) (2.65 kg, 4.63 mol) in
tetrahydrofuran (25 L) was subjected to clear filtration to
remove the heterogeneous particles at 25 °C. The filtrate was
swapped with 2-propanol to prepare a solution of the reactant
in 13.3 L of 2-propanol. To this mixture was added water
(12.54 L) followed by aqueous HCl solution (11 M in water,
0.84 L, 9.26 mol) at 25 5 °C, and the mixture was heated to
65 5 °C until complete conversion was confirmed by HPLC.
The reaction mass was basified with the ammonia solution
(25% w/w in water, 3.34 L, 46.29 mol) and diluted with water
(7.5 L), and the precipitated mass was stirred and filtered to
obtain the title compound in 91% yield.
Purification. To a stirred suspension of crude AZD3264
(1) (1.75 kg, 3.98 mol) in methanol (23.75 L) and water (2.64
L) was added formic acid (0.24 kg, 5.18 mol), and the mixture
was heated to 40 °C for 1.5 h, cooled to 25 °C, and basified
with aqueous ammonia (12.29 M in water, 1.62 L, 19.92 mol).
437.1026. [α]25 −4.60 (c 0.5, DMSO).
D
tert-Butyl (3S)-3-[2-(4-Carbamoyl-5-ureido-2-thienyl)-
5-(3,5-dimethylisoxazol-4-yl)phenoxy]pyrrolidine-1-car-
boxylate (16). A stirred solution of tert-butyl (3S)-3-[2-
bromo-5-(3,5-dimethylisoxazol-4-yl)phenoxy]pyrrolidine-1-car-
boxylate (22) (2.04 kg, 4.11 mol) and tri-isopropyl borate (2.37
kg, 12.33 mol) in tetrahydrofuran (14.40 L) was cooled to −75
°C. To the above mixture was slowly added n-hexyllithium
(33.00%w/w solution in THF, 2.15 kg, 6.99 mol) while the
temperature of the reaction mass was maintained below −65
°C. The reaction completion was confirmed by HPLC. The
reaction mass was diluted with 2-MeTHF (18.00 L) and
quenched with aqueous dilule HCl (1 M, 24.66 L, 24.66 mol).
The organic layer containing [2-[(3S)-1-tert-butoxycarbonyl-
pyrrolidin-3-yl]oxy-4-(3,5-dimethylisoxazol-4-yl)phenyl]-
boronic acid (23) was concentrated to 11.45 L, and 5-bromo-2-
ureido-thiophene-3-carboxamide (6) (0.88 kg, 3.29 mmol),
potassium carbonate (0.86 kg, 6.16 mol), and water (1.98 L)
were added. After degassing of the resultant mixture with
nitrogen, Pd-118 catalyst (0.05 kg, 0.08 mol) was added, and
the mixture was heated to 35 °C. The reaction was monitored
by HPLC. The product was crystallized by adding excess of
water at 50 °C. After the reaction mass cooled to the room
temperature, the product was isolated by filtration.
1
The product was isolated by filtration. H NMR (DMSO-d6,
400 MHz): δ 1.92−2.10 (m, 2H), 2.28 (s, 3H), 2.46 (s, 3H),
2.75−2.82 (m, 1H), 3.00−3.12 (m, 3H), 5.11−5.12 (m, 1H),
6.90 (br, 2H), 7.00−7.03 (m, 2H), 7.30 (br, 1H), 7.70−7.72
(m, 2H), 7.83 (s, 1H), 10.93 (s, 1H). 13C NMR (DMSO-d6,
100.6 MHz): δ 10.54, 11.42, 32.94, 45.51, 53.00, 79.37, 111.76,
114.17, 115.66, 120.70, 121.20, 122.77, 125.39, 126.92, 128.84,
150.12, 152.54, 154.50, 158.13, 165.14, 167.06. DEPT NMR
(DMSO-d6, 100.6 MHz): δ 10.54, 11.43, 32.94, 45.51, 53.01,
79.35, 114.17, 120.70, 121.20, 126.92. HRMS calcd for
C21H24N5O4S (M + H)+: 442.1543, found 442.1554. [α]25
D
−13.80 (c 0.5, DMSO)
ASSOCIATED CONTENT
* Supporting Information
■
S
HPLC and UHPLC methods for AZD3264 and intermediates.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: andiappan.murugan@astrazeneca.com.
■
Palladium Scavenging of 16. A solution of tert-butyl
(3S)-3-[2-(4-carbamoyl-5-ureido-2-thienyl)-5-(3,5-dimethyli-
soxazol-4-yl)phenoxy]pyrrolidine-1-carboxylate (16) (2.89 kg,
4.90 mol) and Quadrasil MP (1.45 kg, 16.04 mol) in 2-
butanone (43.40 L) was heated to 70 °C for 5 h. The resultant
reaction mixture was cooled to 30 °C and filtered through
Celite bed to remove quadrasil and undissolved matter. The
filtrate was concentrated to 14.45 L, crystallized by addition of
n-heptane (28.93 L), and filtered to isolate the product in 94%
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the management team of AstraZeneca for timely
support.
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ABBREVIATIONS
■
Pd-118: dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]
palladium(II); CAS no. 95408-45-0
Pd-101: tetrakis(triphenylphosphine)palladium(0); CAS no.
14221-01-3
Pd-106: dichloro[1,1′-bis(diphenylphosphino)ferrocene]
palladium(II)-dichloromethane adduct; CAS no. 95464-05-4
Neolyst CX21 iPr: allylchloro-[1,3-bis(diisopropylphenyl)-
imidazole-2-ylidene]palladium(II); CAS no. 478980-03-9
2-MeTHF: 2-methyltetrahydrofuran
THF: tetrahydrofuran
DMF: N,N-dimethylformamide
REFERENCES
■
(1) (a) Li, J.; Peet, G. W.; Pullen, S. S. J. Biol. Chem. 1998, 273,
30736. (b) Hu, Y.; Baud, V.; Delhase, M. Science 1999, 284, 316.
(c) Bamborough, P.; Callahan, J. F.; Christopher, J. A.; Kerns, J. K.;
Liddle, J.; Miller, D. D.; Morse, M. A.; Rumsey, W. L.; Williamson, R.
Top. Med. Chem. 2009, 9, 623.
(2) Baxter, A.; Brough, S.; Faull, A.; Johnstone, C.; Mcinally, T.
WO2001058890A1, 2001.
(3) (a) Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel, L.
B.; Chan, J.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J.;
Reider, P. J. Org. Lett. 2006, 8, 1787−1789. (b) Barder, T. E.; Walker,
S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127,
4685−4696. (c) Walker, S. D.; Barder, T. E.; Martinelli, J. R.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871−1876.
(d) Navarro, O.; Kaur, H.; Mahjoor, P.; Nolan, S. P. J. Org. Chem.
2004, 69, 3173−3180. (e) Harkal, S.; Ratabul, F.; Zapf, A.; Fuhrmann,
C.; Riermeier, T.; Monsees, A.; Beller, M. Adv. Synth. Catal. 2004, 346,
1742−1748. (f) Zapf, A.; Jackstell, R.; Rataboul, F.; Reirmeier, T.;
Monsees, A.; Fuhrmann, C.; Shaikh, N.; Dingerdissen, U.; Beller, M.
Chem. Commun. 2004, 38−39. (g) Colacot, T. J.; Shea, H. A. Org. Lett.
2004, 6, 3731−3734. (h) Navarro, O.; Kelly, R. A., III; Nolan, S. P. J.
Am. Chem. Soc. 2003, 125, 16194−16195. (i) Bedford, R. B.; Cazin, C.
S. J.; Hzelwood, S. L. Angew. Chem., Int. Ed. 2002, 41, 4120−4122.
(j) Kataoka, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem.
2002, 67, 5553−5566. (k) Gstottmayr, C. W. K.; Bohm, V. P. W.;
Herdtweck, E.; Grosche, M.; Herrmann, W. A. Angew. Chem., Int. Ed.
2002, 41, 1363−1365. (l) Yin, J.; Rainka, M. P.; Zhang, X.-X;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1162−1163.
(m) Kirshhoff, J. H.; Dai, C.; Fu, G. C. Angew. Chem., Int. Ed. 2002,
41, 1945. (n) Liu, S.-Y.; Choi, M. J.; Fu, G. C. Chem. Commun. 2001,
2408. (o) Li, G. Y.; Zheng, G.; Noonan, A. F. J. Org. Chem. 2001, 66,
8677−8678. (p) Bedford, R. B.; Cazin, C. S. J. Chem. Commun. 2001,
1540−1541. (q) Zapf, A.; Ehrentraut, A.; Beller, M. Angew. Chem., Int.
Ed. 2000, 39, 4153−4155. (r) Bei, X.; Turner, H. W.; Weinberg, W.
H.; Guram, A. S. J. Org. Chem. 1999, 64, 6797−6803. (s) Bei, X.;
Crevier, T.; Guram, A. S.; Jandeleit, B.; Powers, T. S.; Turner, H. W.;
Uno, T.; Weinberg, W. H. Tetrahedron Lett. 1999, 40, 3855−3858.
(4) (a) Billingsley, K.; Barder, T.; Buchwald, S. Angew. Chem., Int. Ed.
2007, 46, 5359−5363. (b) Baudoin, O.; Cesario, M.; Guen
Gueritte, F. J. Org. Chem. 2002, 67, 1199−1207. (c) Baudoin, O.;
Guenard, D.; Guer
́
ard, D.;
́
́
́
itte, F. J. Org. Chem. 2000, 65, 9268−9271.
(d) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron Lett.
1997, 38, 3447−3450.
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