Facile preparation of highly-functionalized, nitrogen-bearing diarylmethanes

Article abstract of DOI:10.1016/j.tetlet.2012.09.112

A palladium-catalyzed cross coupling of nitrogen bearing heterocyclic chloromethyl derivatives with aryl and heteroaryl boronic acids has been developed. In almost all cases, highly efficient cross-couplings were observed at ambient temperature, mitigating unwanted thermally induced side-reactions. The comprehensive substrate scope and respectable yields highlight the synthetic utility of this reaction.

Full text of DOI:10.1016/j.tetlet.2012.09.112

Tetrahedron Letters 54 (2013) 15–20
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile preparation of highly-functionalized, nitrogen-bearing diarylmethanes
Jason R. Schmink a, Matthew T. Tudge b,
⇑
a UPenn/Merck HTE Center, Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania 231 S. 34th Street, Philadelphia, PA 19104-6323, USA
b Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-catalyzed cross coupling of nitrogen bearing heterocyclic chloromethyl derivatives with aryl
and heteroaryl boronic acids has been developed. In almost all cases, highly efficient cross-couplings
were observed at ambient temperature, mitigating unwanted thermally induced side-reactions. The com-
prehensive substrate scope and respectable yields highlight the synthetic utility of this reaction.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 10 September 2012
Accepted 24 September 2012
Available online 13 October 2012
Keywords:
Cross-coupling
Diarylmethanes
Palladium catalysis
Heterocycles
Introduction
detailed examination of the literature revealed only isolated exam-
ples9 of this type of coupling highlighting the need for a more com-
The diarylmethane structural motif is found in a range of bio-
logically active compounds and has been incorporated into a num-
ber of promising pharmaceuticals. As shown in Figure 1, the
diarylmethane substructure is present in Trimethoprim (TMP) 1
and piritrexim (PTX) 2 which are used to treat a wide range of bac-
terial infections1 including treatment against opportunistic infec-
tions caused by Pneumocystic carinii and Toxoplasma gondii in
patients with AIDS.2 Additionally, the diarylmethane moiety plays
a prominent role in a number of antiretroviral therapies targeting
HIV1-Integrase, the enzyme mediating a crucial step in the replica-
tion of HIV.3 Two such examples of small molecules having reached
various stages of clinical development include Shionogi/GSK’s
S-1360 3 and Gilead Science’s GS-9137 (Elviltegravir) 4 which are
currently in Phase III clinical trials for the treatment of HIV.4
Given the wide range of pertinent examples of diarylmethanes,
it is of no surprise that there has been a recent emergence in devel-
oping methodologies to systematically effect the formation of the
carbon–carbon bond linkage of the diarylmethane.5 Since palla-
dium-catalyzed C–C bond formation is one of the most powerful
synthetic tools available to the organic chemist it is also of no sur-
prise that the use of palladium has played a primary role in the
development of new methodologies to afford diarylmethanes.
While there are numerous examples that utilize the robust and
well-explored Suzuki–Miyaura reaction (SMR)6 to generate all car-
bon diarylmethane scaffolds,7 there are relatively few examples of
basic N-heterocylic-halomethyl (N-Het-CH2X) couplings.8 Indeed, a
prehensive study of this substrate class. Furthermore, these
literature examples often require elevated temperatures and/or
strongly basic conditions to achieve useful levels of reactivity thus
resulting in low to moderate yields of the desired products.8,9 To
maximize the productivity of the SMR reaction in library-based
diversity orientated syntheses,10 we required reaction conditions
that are: (i) tolerant of a wide array of functionality, (ii) generally
robust, and (iii) operationally simple. With these guiding principles
NH2
Me
N
OMe
OMe
OMe
OMe
N
N
H2N
N
H2N
N
OMe
Trimethoprim (TMP), 1
Piritrexim (PTX), 2
Cl
O
O
F
O
N
F
OH
CO2H
N
S-1360, 3
MeO
N
N
H
OH
GS-9137 (Elviltegravir), 4
⇑
Corresponding author.
E-mail address: matthew_tudge@merck.com (M.T. Tudge).
Figure 1. Examples of pharmaceutically-active small molecules containing
diarylmethane moiety.
a
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.112

16
J. R. Schmink, M. T. Tudge / Tetrahedron Letters 54 (2013) 15–20
our initial investigations focused on assessing the reactivity of a
novel class of air-stable precatalysts PC1-PC8 developed within
our laboratories, and independently by Buchwald and co-workers
(Scheme 1).11 Complexes such as PC6, when treated with mild
bases at ambient temperature undergo reductive elimination of
carbazole to form active L1Pd(0) catalysts in a highly reproducible
manner.12 This predictable reactivity was successfully exploited by
Buchwald and co-workers in the room-temperature Csp2–Csp2
SMR of sensitive poly-fluorinated aryl boronic acids and aryl-
chlorides.13 An array of biaryl-palladacycle precatalysts bearing
sterically and electronically diverse ligands14 that are known to
facilitate Csp2–Csp3 and/or Csp2–Csp2 bond formation were pre-
pared using the chemistry outlined in Scheme 1. Formation of
Pd(OAc)2
NH2
NH2•HCl
Pd
THF, 60 ºC
(95%)
Cl
5
2
direct isolation
Ph
O
P
L5: XPhos
L1: PPh3
L1-L8,
L6: CataCxium A
L7: P(o-tol)3
L2: P(Cy)3
L3: P(t-Bu)3
L4: SPhos
acetone,
25 ºC
O
O
L8: PA-PPh
L8
: PA-PPh (ref. 16)
the l
-chloro-dimer 515 was readily achieved by heating 2-amino-
PC1: (96%) PC5: (97%)
biphenyl hydrochloride with palladium acetate in THF to afford 5
PC2:
PC3:
PC4:
PC6:
PC7:
PC8:
(95%)
(87%)
(96%)
(94%)
(98%)
(93%)
NH2
in 85% yield after direct isolation from the reaction mixture. Final-
Pd
ly, treatment of
l
-chloro-dimer 5 with phosphines L1-L816 in
L
Cl
acetone, at room temperature, afforded precatalysts PC1-PC8.
Utilizing high-throughput experimentation techniques (HTE)
developed within our laboratories,17 we examined the cross
coupling between 3-picolyl chlorideꢀHCl 5 and the hindered 2,
6-dimethylphenylboronic acid 6a against a range of solvents and
aqueous bases (8 precatalysts ꢁ 4 aqueous bases ꢁ 6 co-solvents
ꢁ 2 temperatures = 384 discrete reaction conditions; Fig. 2). The
choiceof 6 was based onthe propensity of this compoundto undergo
base promoted polymerization through quaternization of the
pyridine nitrogen, especially at the elevated temperatures routinely
employed for Csp2–Csp3 SMR reactions.7–9 Finally, while significant
excess of the boronic acid is commonly utilized in cross-coupling
reactions, we opted to limit the excess boronic acid to 1.1 equiv to
increase the practicality of the transformation.
Scheme 1. Preparation of palladium aminobiphenyl precatalysts. SPhos = 2-Dicy-
XPhos = 2-dicyclohexylphosphino-
20,40,60-triisopropylbiphenyl, CataCXium A = di(1-adamantyl)-n-butylphosphine.
clohexylphosphino-20,60-dimethoxybiphenyl,
PA-PPh = 1,3,5,7-tetramethyl-2,4,8-trioxa-6-phenylphospadamantyl.
in mind, we sought to develop a general SMR based synthesis of N-
heterocyclic diarylmethanes containing basic nitrogen motifs.
Herein, we report the results of our investigations toward this
important goal.
Results & discussion
Since pre-defined catalysts reproducibly generated under mild
conditions may offer enhanced levels of robustness and activity,
In an effort to select the most generalized set of conditions from
the 384 reactions shown in Figure 2, we focused our analysis on
PPh3
PCy3
P(t-Bu)3
SPhos
XPhos
CataCXium A
P(o-Tol)3
PA-PPh
PPh3
PCy3
P(t-Bu)3
SPhos
XPhos
CataCXium A
P(o-Tol)3
PA-PPh
Figure 2. Initial screen and graphical representation of percentage yield across 384 reactions. Conditions: 0.1 M (10.0
lmol 6, 11.0 lmol 7), 4 equiv aqueous base, 2 mol %
PC1-PC8. Results in blue run at 35 °C; red at 50 °C. For comprehensive quantitative data, see the Supporting Information.

J. R. Schmink, M. T. Tudge / Tetrahedron Letters 54 (2013) 15–20
17
Table 1
Cross-coupling of arylboronic acids with various heterobenzyl chlorides
2% PC-8
5:4 THF / H2O
B(OH)2
HetAr
HetAr
Ar
Cl
+
Ar
4 equiv. K3PO4
35 °C, 20 h
Entry
1
HetAr
Aryl (Ar)
Product
Yield (%)
86a (85)
N
N
N
CF3
CF3
2
3
4
5
72a (75)
77a (82)
83a
N
CF3
CF3
F
F
N
N
N
F
F
OMe
OMe
N
N
OMe
OMe
89a
F
F
N
N
F
F
Cl
Cl
6
81a
N
Cl
Cl
S
S
7
8
9
94b
71b
86b
N
N
O
N
N
N
O
N
N
O
N
O
NHAc
10
11
94b
90b
N
N
NHAc
O
O
O
N
N
O
O
O
N
N
Me
Me
(continued on next page)

18
J. R. Schmink, M. T. Tudge / Tetrahedron Letters 54 (2013) 15–20
Table 1 (continued)
Entry
HetAr
N
Aryl (Ar)
Product
Yield (%)
66b (91)
12
13
O
N
O
O
O
O
OMe
97b
N
O
OMe
N
F
F
14
15
16
0
N
F
Cl
N
N
N
F
Cl
Cl
Cl
0
0
N
N
iPr
iPr
iPr
iPr
iPr
iPr
All yields refer to isolated yields. (IPA as cosolvent). [1.5 Equiv boronic acid].
a
Isolated as the HCl salt.
Isolated after column chromatography.
b
reactions generating coupled product 8 in >90% assay yield.18 At
both 35 °C and 50 °C PC-8 provided 8 >90% yield across the widest
range of base/solvent combinations (8/24 and 17/24 respectively),
clearly making it the precatalyst of choice.
Potassium phosphate proved to be the most general base
affording >90% assay yield of coupled product 8 in 32/96 precata-
lyst/solvent/temperature combinations. In contrast, Cs2CO3,
Na2CO3, and KF only gave >90% assay yield of 7 in 15/96, 14/96,
and 1/96 precatalyst/solvent/temperature combinations respec-
tively. THF, dioxane, and IPA all proved to be effective solvents
affording 8 in >90% yield 12/64, 15/64, and 12/64 precatalyst, base,
and temperature combinations. Ultimately, THF was selected as
the reaction solvent due to the lower toxicity relative to dioxane
and its enhanced solvation properties relative to IPA.
With a generalized set of conditions in hand (2 mol % PC-L8,
1.1 equiv boronic acid, 5:4 THF:H2O, 4 equiv K3PO4), we turned
our attention to evaluating the substrate scope of the reaction (Ta-
ble 1). Special attention was paid to potentially problematic boro-
nic acid coupling partners, especially electron-poor, sterically
demanding, or those particularly prone to deboronation. A variety
of arylboronic acids were coupled with 6 to provide the corre-
sponding SMR adducts in good yields (Table 1, entries 1–6). In
addition, the optimized conditions smoothly coupled pyrazole
and isoxazole chloromethyl derivatives with a range or boronic
acids to afford the resultant products in excellent yields (Table 1,
entries 7–13).
The limitations of this methodology were met in the attempted
cross-coupling of 2,6-difluoro- or 2,6-dichlorophenylboronic acid
with 6 (Table 1, entries 14 and 15). In these instances, protodebor-
onation proved far more facile than the desired cross-coupling. In
addition, the highly sterically-hindered boronic acid 2,4,6-tri-
isopropylphenylboronic acid also proved problematic yielding
<1% of the desired product (Table 1, entry 16).
In the case of 2-chloromethyl substituted heterocycles, we ob-
served a sluggish conversion into the desired product when the
reactions were carried out at 35 °C. By increasing the reaction tem-
perature to 60 °C, the desired coupling products could be furnished
in synthetically useful yields (Table 2, entries 1–6). Indeed, under
our optimized reaction conditions even electron rich pyridines pro-
vided the corresponding products in good yield without polymer-
ization of the starting materials (Table 2, entries 5 and 6). We
speculate that after the oxidative insertion of palladium into the
C–Cl bond, the lone pair of the pyridine nitrogen atom may co-
ordinate with the palladium-(II) center thereby attenuating the
electrophilic character of the metal center necessitating higher
reaction temperatures to facilitate reductive elimination.19 This
problem appears to be exacerbated when using a 2-chloromethyl
pyrimidine derivative (entry 7) where two opportunities for coor-
dination exist.
Summary & conclusions
The benefits of the very clean reaction profile were exploited in
many cases by simply isolating the HCl salt of the products after a
standard aqueous-organic workup, eliminating the need for chro-
matographic purification of substrates that contained a basic nitro-
gen and lacking acid sensitive functionality, (entries 1–6).
Interestingly, Csp2–Cl bonds were well tolerated (entry 6) with
no evidence of the orthogonal cross-coupling product. In instances
where competitive protodeboronation proved to be problematic
(entry 12), an improvement in yield could be realized by simply
increasing the 2-benzofuranboronic acid loading to 1.5 equiv.
In summary, we have developed a generalized set of conditions
for the Suzuki coupling of a diverse array of heterocyclic-chloro-
methyl derivatives. Notably, the mild conditions and the use of a
novel palladium precatalyst lend themselves perfectly to diver-
sity-orientated synthesis by simplifying parallel operations and
imparting a greater overall robustness. Studies in order to under-
stand better the nature of the active catalysts and the attenuated
reactivity of the 2-picolyl derivatives are underway and will be re-
ported in due course.

J. R. Schmink, M. T. Tudge / Tetrahedron Letters 54 (2013) 15–20
19
Table 2
Top: cross-coupling of arylboronic acids with 2-picolyl chloride derivatives required an elevated reaction temperature and/or extended reaction times
2% PC-8
5:4 THF / H2O
B(OH)2
+
HetAr
Cl
Ar
4 equiv. K3PO4
60 °C, 20 h
Ar
N
Entry
1
HetAr
Aryl (Ar)
Product
Yield (%)
77
N
N
F
F
2
3
72
66
N
N
N
N
F
F
F
F
OMe
OMe
4
5
6
61
70
74
N
O
N
O
F
CF3
F
CF3
N
OMe
N
OMe
NHAc
OMe
OMe
NHAc
OMe
N
N
OMe
OMe
N
N
N
N
7
24
OMe
(a) Boronic acid; (b) pinacol ester; (c) isolated as the HCl salt; (d) isolated by column chromatography.
Roberge, J. Y.; Seed, B.; Chen, Y. Bioorg. Med. Chem. Lett. 2011, 21, 4465; (g) Yap,
A. J.; Chan, B.; Yuen, A. K. L.; Ward, A. J.; Masters, A. F.; Maschmeyer, T.
ChemCatChem 2011, 3, 1496.
Acknowledgment
JRS acknowledges the National Science Foundation for financial
support (NSF-GOALI 0848460). Dr. Spencer Dreher is thanked for
helpful discussions.
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