One-pot C-N/C-C cross-coupling of methyliminodiacetic acid boronyl arenes enabled by protective enolization

Article abstract of DOI:10.1021/ol302702q

Iterative cross-coupling is a highly efficient and versatile strategy for modular construction in organic synthesis, though this has historically been demonstrated solely in the context of C-C bond formation. A C-N cross-coupling of haloarene methyliminodiacetic acid (MIDA) boronates with a wide range of aromatic and aliphatic amines is reported. Successful cross-coupling of aliphatic amines was realized only through protective enolization of the MIDA group. This reaction paradigm was subsequently utilized to achieve a one-pot C-N/C-C cross-coupling sequence.

Full text of DOI:10.1021/ol302702q

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5578–5581
One-Pot CꢀN/CꢀC Cross-Coupling of
Methyliminodiacetic Acid Boronyl Arenes
Enabled by Protective Enolization
Jonathan E. Grob,* Michael A. Dechantsreiter, Ritesh B. Tichkule,
Michael K. Connolly, Ayako Honda, Ronald C. Tomlinson, and Lawrence G. Hamann
Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue,
Cambridge, Massachusetts 02139, United States
jonathan.grob@novartis.com
Received September 29, 2012
ABSTRACT
Iterative cross-coupling is a highly efficient and versatile strategy for modular construction in organic synthesis, though this has historically been
demonstrated solely in the context of CꢀC bond formation. A CꢀN cross-coupling of haloarene methyliminodiacetic acid (MIDA) boronates with a
wide range of aromatic and aliphatic amines is reported. Successful cross-coupling of aliphatic amines was realized only through protective
enolization of the MIDA group. This reaction paradigm was subsequently utilized to achieve a one-pot CꢀN/CꢀC cross-coupling sequence.
Metal catalyzed cross-couplings have for decades been
among the most practical and widely used methodologies
in the synthesis of natural products and other biologically
relevant small molecules.1 In particular, the ubiquitous
application of sp2ꢀsp2 cross-couplings in the preparation
of drug-like molecules in pharmaceutical research and
development2 has had a transformative impact on the
syntheticstrategiesemployed by medicinalchemists, which
is reflected in the chemical space occupied by pharma
compound collections and screening libraries.3 This pro-
cess often involves the application of a building block
approach to target compound synthesis where shelf stable,
commercially available intermediates can be installed in
a modular and iterative fashion onto a core scaffold.4
Cross-coupling methodology is uniquely suited to this
application, and in recent years the possibility for iterative
cross-couplings has been realized.5 One especially note-
worthy paradigm enabling such iterative applications of
cross-couplings is the use of air-stable and reagent tolerant
methyliminodiacetic acid (MIDA) protected boronates
pioneered by Burke, the power of which has been demon-
strated in several very efficient natural product syntheses.6
We have also applied MIDA boronate chemistry in tele-
scoped syntheses of drug-like compound arrays.7
Figure 1. CꢀN cross-coupling approach to the preparation and
(1) (a) Metal Catalyzed Cross Coupling Reactions; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2008. (b) Bolm, C. J. Org.
Chem. 2012, 77, 5221–5223.
diversification of boron-functionalized amino-aryls.
To date, iterative cross-coupling methodologies of bo-
ronate derivatives have focused exclusively on the formation
(2) (a) Magano, J.; Dunetz, J. R. Chem. Rev. 2011, 111, 2177–2250.
(b) Torborg, C.; Beller, M. Adv. Synth. Catal. 2009, 351, 3027–3043.
(3) (a) Cooper, T. W. J.; Campbell, I. B.; Macdonald, S. J. F. Angew.
Chem., Int. Ed. 2010, 49, 8082–8091. (b) Roughley, S. D.; Jordan, A. M.
J. Med. Chem. 2011, 54, 3451–3479. (c) Walters, W. P.; Green, J.; Weiss,
J. R.; Murcko, M. A. J. Med. Chem. 2011, 54, 6405–6416.
(4) Burke, M. D.; Berger, E. M.; Schreiber., S. L. Science 2003, 302,
613–618.
(5) (a) Wang, C.; Glorius, F. Angew. Chem., Int. Ed. 2009, 48, 5240–
5246. (b) Gillis, E. P.; Burke., M. D. Aldrichimica Acta 2009, 42, 17–27.
(c) Denmark, S. E.; Tymonko, S. A. J. Am. Chem. Soc. 2005, 127, 8004–
8005.
r
10.1021/ol302702q
Published on Web 10/23/2012
2012 American Chemical Society

of CꢀC bonds. Advancing this iterative synthetic strategy
to include CꢀN or CꢀO cross-couplings would substantially
expand the chemical space that can be accessed with this
highly modular approach, including that occupied by many
pharmaceutically active compounds containing C(sp2)ꢀN
bonds. Given the wide range of transformations achievable
from boron-functionalized aryls,8 this diversification strat-
egy could take advantage of the well-established cross-
coupling applications of boronates, as well as emerging
methods in the fields of CꢀH functionalization9 and metal
catalyzed fluorination10 and trifluoromethylation11 that
utilize boronic acid precursors (Figure 1).
other closely related biaryl phosphine precatalysts X-Phos
(entry 2) and Brett-Phos (entry 4), which were only mod-
erately successful. A variety of bases were also screened,
though only tripotassium phosphate afforded high
yields of the desired aminated MIDA boronate. While
the strong base LiHMDS (entry 7) did promote the desired
N-arylation at rt, the MIDA group was hydrolyzed under
these conditions.
Table 1. Optimization of the CꢀN Cross-Coupling of Haloaryl
MIDA Boronates
As an initial investigation into the feasibility of this
approach we assessed the reactivity and stability of a
haloaryl MIDA boronate under standard Buchwald
CꢀN cross-coupling conditions (Table 1).12 While the
CꢀN coupling failed to progress to full conversion, the
MIDA boronate was completely stable under the reaction
conditions. This early result, coupled with the known
reagent tolerance,13 ease of preparation,14 and the ability
of MIDA boronates to participate in slow release cross-
couplings,15 led us to further develop optimized conditions
for this CꢀN cross-coupling.16 Noteworthy observations
from the optimization efforts (Table 1) include the sig-
nificant improvement realized by applying the palladacyc-
lic precatalyst tert-butyl X-Phos Pd G1 (entry 3) developed
by the Buchwald group.17 This system proved superior to
entry solvent
Pd-source ligand
base
conversiona
1
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
Pd(OAc)2, X-Phos
X-Phos Pd G1
K3PO4
K3PO4
42%
2
33%
3
t-Bu-X-Phos Pd G1 K3PO4
Brett-Phos Pd G1 K3PO4
95% (62%)d
60%
4
5
t-Bu-X-Phos Pd G1 K2CO3
t-Bu-X-Phos Pd G1 Cs3CO3
t-Bu-X-Phos Pd G1 LiHMDS
t-Bu-X-Phos Pd G1 K3PO4
t-Bu-X-Phos Pd G1 K3PO4
t-Bu-X-Phos Pd G1 K3PO4
59%
6
76%
7
95%b,c
95%
8
(6) (a) Fujii, S.; Chang, S. Y.; Burke., M. D. Angew. Chem., Int. Ed.
2011, 50, 7862–7864. (b) Woerly, E. M.; Cherney, A. H.; Davis, E. K.;
Burke, M. D. J. Am. Chem. Soc. 2010, 132, 6941–6943. (c) Fujita, K.;
Matsui, R; Suzuki, T.; Kobayashi, S. Angew. Chem., Int. Ed. 2012, 51,
7271–7274.
9e
10f
MeCN
MeCN
0%
95%c
a All reactions were run with 1 equiv of aryl halide, 1.2 equiv of
aniline, 5 equiv of base, and 5 mol % Pd-catalyst. Conversion was
determined by UV-HPLC. b Free boronic acid product was observed.
c Reaction run at 25 °C. d Isolated yield. e ArꢀB(OH)2 was used instead
of MIDA boronate. f ArꢀBF3K was used instead of MIDA boronate.
(7) (a) Grob, J. E.; Nunez, J.; Dechantsreiter, M. A.; Hamann, L. G.
J. Org. Chem. 2011, 76, 4930–4940. (b) Grob, J. E.; Dechantsreiter,
M. A.; Nunez, J.; Hamann, L. G. J. Org. Chem. 2011, 76, 10241–10248.
(8) Qiao, J.; Lam, P. Y. S. Boronic Acids: Preparation and Applica-
tions in Organic Synthesis, Medicine and Materials, 2nd ed.; Wiley-VCH:
Weinheim, 2011; pp 315ꢀ361.
(9) (a) Engle, K. M.; Thuy-Boun, P. S.; Dang, M.; Yu, J.-Q. J. Am.
Chem. Soc. 2011, 133, 18183–18193. (b) Seiple, I. B.; Su, S.; Rodriguez,
R. A.; Gianatassio, R.; Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am.
Chem. Soc. 2010, 132, 13194–13196. (c) Nishikata, T.; Abela, A. R.;
Huang, S.; Lipshutz, B. H. J. Am. Chem. Soc. 2010, 132, 4978–4979.
(10) (a) Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem., Int. Ed.
2008, 47, 5993–5996. (b) Furuyu, T.; Ritter, T. Org. Lett. 2009, 11, 2860–
2863. (c) Brenzovich, W. E., Jr.; Brazeau, J.-F.; Toste, F. D. Org. Lett.
2010, 12, 4728–4731.
With these optimized conditions we set out to evaluate
the scope of the CꢀN couplings. Successful aminations
were observed with a variety of aniline and heterocyclic
amine nucleophiles as well as heteroaryl MIDA boronates
(Figure 2). The versatility of the procedure is further
underscored by the successful cross-coupling reactions in
the presence of commonly encountered functionality, in-
cluding ester (6), sulphone (8), pyridines (4ꢀ7), and a
heterocyclic core structure (4). It bears mention, however,
that this reaction is sensitive to steric demands on both the
MIDA boronate (9) and the aryl amine (10) and is
completely inoperable on both primary and secondary
aliphatic amines (13, 14) under these conditions.
To address this limitation we first considered base
strength as a probable cause of lack of reactivity, as the
only base successful in the aniline couplings was the
strongest of the commonly available, non-nucleophilic,
inorganic bases.18 We hypothesized that the switch from
aryl to aliphatic amines impacted the relative acidity of the
(11) (a) Liu, T.; Shen, Q. Org. Lett. 2011, 13, 2342–2345. (b) Senecal,
T. D.; Parsons, A. T.; Buchwald, S. L. J. Org. Chem. 2011, 76, 1174–
1176. (c) Litvinas, N. D.; Fier, P. S.; Hartwig, J. F. Angew. Chem., Int.
Ed. 2012, 51, 536–539. (d) Novak, P.; Lishchynskyi, A.; Grushin, V. V.
Angew. Chem., Int. Ed. 2012, 51, 7767–7770.
(12) X-Phos Pd-G1 refers to Buchwald’s phenethylamine derived
precatalyst (see ref 17).
(13) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2008, 130, 14084–
14085.
(14) (a) Ballmer, S. G.; Gillis, E. P.; Burke, M. D. Org. Synth. 2009,
86, 344–359. (b) Dick, G. R.; Knapp, D. M.; Gillis, E. P.; Burke, M. D.
Org. Lett. 2010, 12, 2314–2317.
(15) (a) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc.
2009, 131, 6961–6963. (b) Lennox, A. J. J.; Lloyd-Jones, G. C. Isr. J.
Chem. 2010, 50, 664–674. (c) Lennox, A. J. J.; Lloyd-Jones, G. C. J. Am.
Chem. Soc. 2012, 134, 7431–7441.
(16) For another approach to CꢀN coupling on aryl boronate
containing substrates, see: (a) Holmes, D.; Chotana, G. A.; Maleczka,
R. E., Jr.; Smith, M. R., III. Org. Lett. 2006, 8, 1407–1410. (b) Shi, F.;
Smith, M. R., III; Maleczka, R. E., Jr. Org. Lett. 2006, 8, 1411–1414.
(17) (a) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc.
2008, 130, 6686–6687. (b) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am.
Chem. Soc. 2010, 132, 14073–14075.
(18) Ripin, D. H.; Evans, D. A. Table of pKa’s of Inorganic and Oxo
Acids http://evans.harvard.edu/pdf/evans_pka_table.pdf (accessed
October 16, 2012).
Org. Lett., Vol. 14, No. 21, 2012
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Table 2. Effect of Enolization on CꢀN Couplings of Aliphatic
Amines
entry
solvent
temp
80 °C
25 °C
25 °C
base
conversiona
1
MeCN
MeCN
THF
K3PO4
0%
2
LiHMDS
LiHMDS
LiHMDS
>95%b
>95%d
>95% (80)
3c
4c
THF
ꢀ30 to þ25 °C
a All reactions were run with 1 equiv of arylbromide, 1.2 equiv of
amine, 5 equiv of base, and 5 mol % t-BuX-Phos Pd G1. Conversion was
determined by UV-HPLC. Isolated yield in parentheses. b Free boronic
acid product was observed. c Anhydrous conditions. d A ratio of 1:1
MIDA boronate to free boronic acid was observed.
evidence of enolate formation20 validated our hypothesis
and thus enabled the cross-coupling of aliphatic amines
and MIDA boronates which was completely inoperable
under all other conditions.
These conditions proved to be quite general21 (Figure 3)
and enabled access to a variety of amine functionalized
boron containing building blocks primed for further deriv-
atization. Of particular interest is the range of heterocyclic
coupling partners that participate in the amination reaction,
as well as the regioselective amination of dichloropyridine
substrate (15), presumably due to the extreme steric demand
imposed by the MIDA boronate on the ortho-halide.
Aware that the Buchwald precatalysts utilized in the
transformations developed above are also capable of
catalyzing SuzukiꢀMiyaura cross-couplings (SMCCs),22
we set out to explore the potential for developing a one-pot
sequence to effect both cross-coupling steps, in keeping
with efforts aimed at developing efficient step-economical,
greener methods for medicinal and process chemistry
applications.23 We noted the lack of literature precedent
for the use of tert-butyl X-Phos in SMCCs, so we chose to
introduce the second generation X-Phos derived precata-
lyst at the second step of this two-step one-pot procedure.
In the event we were gratified to observe successful SMCC,
realized merely by dosing the CꢀN coupling reaction
mixture with an aryl halide, aqueous base, and the X-Phos
Pd G2 (Figure 4).24
Figure 2. Investigation of substrate scope in the N-arylation of aryl
amines. All reactions were run with 1 equiv of aryl halide, 1.2 equiv
of amine, 5 equiv of K3PO4, and 5 mol % t-BuX-Phos Pd G1.
amine proton in the amine-Pd(II) complex and, therefore,
that the less acidic PdꢀN(R)ꢀH proton in the case of
aliphatic amines might require a stronger base to promote
reductive elimination.19 However, given the presumed
incompatibility of the MIDA protecting group with strong
bases, balancing these reactivities appeared to be a for-
midable challenge. We consequently revisited our original
optimization (Table 2) and focused on the reaction with
LiHMDS (Table 1, entry 7), which had previously pro-
vided successful CꢀN coupling of an aniline, albeit with
the destruction of the MIDA group. These conditions
applied to an aliphatic amine under anhydrous conditions
did afford the desired product as a 1:1 mixture of MIDA
boronate and free boronic acid despite the strict exclusion
of water. We hypothesized that a further degree of protec-
tion could be imparted if the MIDA group were enolized,
rendering it impervious to nucleophilic attack. We gener-
ated the enolate under controlled conditions at low tem-
perature which yielded the desired MIDA boronate
containing product with little evidence of hydrolysis.
This result combined with further NMR spectroscopic
(20) See Supporting Information for evidence in support of the
enolate formation.
(21) The improved conditions were ineffective on the aryl amines.
(22) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461–
1473.
(23) (a) Desai, A. A.; Molitor, E. J.; Anderson, J. E. Org. Process Res.
Dev. 2012, 16, 160–165. (b) Anastas, P. T.; Warner, J. C. Green
Chemistry: Theory and Practice; Oxford University Press: New York,
1998; p 30.
(19) By analogy to the Pd(II) precatalysts reported by the Buchwald
group16 which are activated by reductive elimination from the Pd(II)
center. The 2-amino biphenyl derived second generation precatalyst is
activated by K3PO4 at ambient temperature, whereas the phenethyl-
amine derived first generation precatalyst requires NaOt-Bu for ambient
temperature activation.
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Org. Lett., Vol. 14, No. 21, 2012

Figure 3. CꢀN couplings with aliphatic amines. All reactions
were run with 1 equiv of aryl halide, 1.2 equiv of amine, 5 equiv
of LiHMDS, and 5 mol % t-BuX-Phos Pd G1. All yields are for
isolated materials and are reported relative to the MIDA boronate.
These conditions were then applied to a range of cou-
pling partners with varying electronics and sterics, as well
as heterocyclic substrates, affording access to a wide
product scope in good overall yields. The one-pot proce-
dure worked well on both electron-rich haloaromatic
coupling partners (27, 28) and electron-deficient haloaro-
matics (35). Heterocyclic systems performed equally effi-
ciently (25, 26, and 29). Aryl amines behave in a similar
way, where after the CꢀN coupling (as in Figure 2) the
reaction mixture is subjected to in situ SMCC and desired
products are obtained for both electron-rich (30) and
electron-poor aryl halides (31). To further highlight the
utility of this approach in a medicinal chemistry context we
applied this procedure to the synthesis of a histamine H3
receptor agonist (37),25 which was prepared ingoodoverall
yield from commercially available materials in a single
synthetic operation.
Figure 4. Two-step, one-pot cross coupling sequence. The in situ
SMCC used 1.5 equiv of aryl halide, 3 equiv of base, and 5 mol %
X-Phos Pd G2. Yields are reported over two steps relative to the
MIDA boronate. For 31 and 37, X-Phos Pd G1 was used for the
CꢀN coupling and no second addition of Pd was required. The
SMCC was run at 50 °C for 32 and 33 and at 80 °C for 31.
We have developed a general approach to selective CꢀN
cross-coupling of bifunctional arenes and report an effi-
cient and versatile application of BuchwaldꢀHartwig cou-
plings in the presence of boronic acid derivatives. In the
course of our investigation we discovered a novel mode of
protection for MIDA boronates. This enolization strategy
uniquely enables access to the products of CꢀN cross-
coupling of aliphatic amines and aryl halides bearing
a MIDA boronate. We have further demonstrated the
power of this methodology in a one-pot, two-step, iterative
CꢀN/CꢀC cross-coupling sequence utilizing in situ release
of the masked boronic acid. Future investigations will
seek to develop the paradigm of protective enolization of
MIDA boronates in varied contexts.
Acknowledgment. The authors thank Prof. Martin
Burke at the University of Illinois and Dr. Jorge Garcia-
Fortanet at Novartis for helpful discussions.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(24) Our initial attempts to perform this reaction with a single dose of
Pd-catalyst resulted in limited success. Cross-coupling sequences were
low yielding and/or narrow in scope.
(25) Zhao, C.; Sun, M.; Bennani, Y. L.; Miller, T. R.; Witte, D. G.;
Esbenshade, T. A.; Wetter, J.; Marsh, K. C.; Hancock, A. A.; Brioni,
J. D.; Cowart, M. D. J. Med. Chem. 2009, 52, 4640–4649.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
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