Palladium catalyzed α-arylation of methyl isobutyrate and isobutyronitrile: an efficient synthesis of 2,5-disubstituted benzyl alcohol and amine intermediates

Article abstract of DOI:10.1016/j.tetlet.2006.09.059

Several 2,5-disubstituted benzyl alcohols containing a functionalized t-butyl moiety were synthesized via palladium catalyzed α-arylation of methyl isobutyrate and butyronitrile on synthetically useful scales. The resulting benzyl alcohols could then be further elaborated to benzyl amines or other desirable intermediates.

Full text of DOI:10.1016/j.tetlet.2006.09.059

Tetrahedron Letters 47 (2006) 8021–8024
Palladium catalyzed a-arylation of methyl isobutyrate and
isobutyronitrile: an efficient synthesis of 2,5-disubstituted
benzyl alcohol and amine intermediates
Rupa Shetty and Kristofer K. Moffett*
Locus Pharmaceuticals, Inc., Four Valley Square, 512 Township Line Road, Blue Bell, PA 19422, USA
Received 29 August 2006; revised 8 September 2006; accepted 12 September 2006
Available online 2 October 2006
Abstract—Several 2,5-disubstituted benzyl alcohols containing a functionalized t-butyl moiety were synthesized via palladium
catalyzed a-arylation of methyl isobutyrate and butyronitrile on synthetically useful scales. The resulting benzyl alcohols could then
be further elaborated to benzyl amines or other desirable intermediates.
Ó 2006 Elsevier Ltd. All rights reserved.
OR1
OR1
Locus Pharmaceuticals uses a fragment based approach
which utilizes a proprietary set of computational meth-
ods to discover leads in generating new therapies for
various diseases. As a result, some of the compounds
that come out of our computational efforts are structur-
ally more elaborated than traditional lead starting
materials or intermediates. In order to access these inter-
mediates, methods must be found to efficiently construct
these more complex compounds to support the synthesis
of novel drug-like leads.
NC
NC
NC
R1 = H, Bn
OR1
OR1
NH2
R2
CHO
R1 = alkyl, Bn , etc.
R2 = CN, CO2CH3
One such series of intermediates is a set of 2,5-substi-
tuted benzyl amines where a t-butyl derived substituent
was to be incorporated as shown in Figure 1. Such an
arrangement of substitution and functionality led us to
evaluate several synthetic schemes.
Scheme 1. Synthesis involving formylation as the key step.
directed formylation as the key step (Scheme 1). The
formyl moiety could then undergo reductive amination
to give the desired benzyl amine. Examination of this
strategy using 4-hydroxyphenyl acetonitrile under a
variety of conditions,1 however, was unsuccessful in giv-
ing the desired formylated product (Scheme 2). Either
The first route envisioned the alkylation of 4-hydroxy-
phenyl acetonitrile followed by hydroxyl or alkoxy
OR
OR
NC
NC
CHO
R = H, Bn
Figure 1. 2,5-Substituted benzyl amines containing a t-butyl derived
moiety.
Scheme 2. Reagents and conditions: R = H (a) paraformaldehyde,
SnCl4, DIEA, CH3CN, 120 °C microwave; (b) paraformaldehyde,
MgCl2, DIEA, CH3CN, reflux; (c) NaOH, H2O, CHCl3, reflux;
R = Bn and (d) dichloromethyl methyl ether, TiCl4, 0°–rt.
*
Corresponding author. Tel.: +1 215 358 2016; fax: +1 215 358
2030; e-mail: kmoffett@locuspharma.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.059

8022
R. Shetty, K. K. Moffett / Tetrahedron Letters 47 (2006) 8021–8024
mo-2-hydroxybenzaldehyde was alkylated with benzyl
bromide or 3-(chloromethyl)pyridine to give 1a and
1b. These aldehydes, along with commercially available
1c, were reduced to the alcohol and protected to provide
intermediates 3a–c.
With the aryl bromides 3a–c and commercially available
4-bromo-2-methylbiphenyl in hand, we proceeded to
explore the palladium catalyzed enolate coupling. We
chose a catalyst preparation utilizing the easily handled
and air stable Pd2(dba)3/Pd(tBu3P)2 system.2b,3 As seen
in Table 1, the reaction of aryl bromides with methyl
isobutyrate enolate (generated using lithium dicyclo-
hexylamide) in the presence of Pd2(dba)3 and Pd(tBu3P)2
provided the corresponding esters 4–7 in excellent yields.
We were able to carry out these transformations on syn-
thetically useful scales (1–5 mmol of starting material).
The reaction rates were much faster than those reported
(3 h for most reactions compared to 8–24 h) with no
reduction in yields.2b
Scheme 3. Synthesis involving palladium catalyzed enolate addition as
the key step.
starting material was recovered or other unidentifiable
material was obtained.
Our second approach envisioned using a metal mediated
coupling of an enolate to an appropriately functional-
ized aryl bromide (Scheme 3). A search of the literature
revealed that Pd0 complexes could be used to catalyze
the addition of enolates to aryl halides.2 The desired
functionalized t-butyl group could be introduced via this
chemistry using isobutyl ester and nitrile enolates. The
appropriate chemistries could then be used to arrive at
the desired benzyl amines.
The corresponding reaction with isobutyronitrile was
performed using the reported conditions2a giving a good
yield of the desired nitrile 8 (Scheme 5).
Compound 6 was converted into ether 10 (Scheme 6) via
hydrogenolysis of the benzyl group followed by alkyl-
ation of the resulting phenol 9. Using this methodology,
The synthesis of the necessary intermediates proceeded
as shown in Scheme 4. Commercially available 5-bro-
OH
OR1
OR1
OR1
CHO
CHO
OH
OR2
c
a or b
d or e
Br
Br
Br
Br
1a: R1 = Bn
1b: R1 = 3-pyridyl
83%
2a: R1 = Bn
3a: R1 = Bn, R2 = SEM
98%
89% (two steps)
2b: R1 = 3-pyridyl
2c: R1 = CH3
3b: R1 = 3-pyridyl, R2 = TBDPS
76% (two steps)
1c: R1 = CH3
3c: R1 = CH3, R2 = SEM
92% (two steps)
Scheme 4. Reagents and conditions: (a) BnBr, K2CO3, acetone, 60 °C; (b) 3-(chloromethyl)pyridine, Cs2CO3, DMF, 100 °C; (c) NaBH4, THF,
MeOH, 0 °C–rt; (d) SEMCl, DIEA, DCM and (e) TBDPSCl, imidazole, DCM, DMF.
Table 1. Palladium catalyzed coupling of methyl isobutyrate enolate to aryl bromidesa
R1
R1
LiNCy2
Pd2(dba)3, Pd(tBu3P)2
toluene, r.t.
R2
R2
+
CO2CH3
Br
CO2CH3
Entry
R1
R2
Pd2(dba)3 (mol %)
Pd(tBu3P)2 (mol %)
Compound
Yieldb (%)
1
2
3
4
OCH2(3-Pyridyl)
CH2OTBDPS
CH2OSEM
CH2OSEM
CH3
0.8
0.7
2.0
0.8
3.5
3.0
3.2
3.8
4
5
6
7
87
74
72
94
OCH3
OBn
Ph
a Typical conditions: To a flask containing 2.5 M n-BuLi (1.3 mmol) in hexanes under argon at 0 °C was added dicyclohexylamine (1.3 mmol). The
ice bath was removed and the mixture was stirred at rt. (Alternatively, LiNCy2 can be made separately and stored as a solid until use.) To the
mixture was added a solution of ester (1 mmol) in 1 mL toluene. This second mixture was stirred at rt for at least 10 min, then was added to a flask
containing aryl bromide, Pd2(dba)3 and Pd(tBu3P)2 in 1.5 mL toluene under argon. The final mixture was stirred at rt. After 3–24 h, the reaction
was diluted with water and extracted with EtOAc. The organic layers were washed with brine, dried over anhyd. Na2SO4, filtered and concentrated.
Purification was by flash column on silica gel using EtOAc:hexanes.
b Isolated yields.

R. Shetty, K. K. Moffett / Tetrahedron Letters 47 (2006) 8021–8024
8023
triphenylphosphine gave the desired amines 13a–e in
an overall good yield. As noted, the attempted palla-
dium catalyzed enolate additions on an aryl bromide
containing the azide resulted in the displacement of
the azide through O-alkylation of the ester enolate.
CN
OCH3
OCH3
CN
NaHMDS
Pd(OAc)2, BINAP
OSEM
OSEM
toluene
100 °C
61%
Br
3c
8
The biphenyl ester 7 (Table 1, entry 4) was converted to
amine 16 by first brominating the benzylic methyl using
N-bromosuccinimide and benzoyl peroxide (Scheme 8).
The bromide of 14 was then displaced by azide, giving
15, which was reduced by triphenylphosphine to give
the desired amine 16.
Scheme 5. Isobutylnitrile enolate addition.4
N
OBn
OH
O
OSEM
OSEM
OSEM
The benzyl amines 13a–e and 16 were subsequently used
as building blocks in the synthesis of more complex,
drug-like molecules.
a
b
CO2CH3
CO2CH3
CO2CH3
6
9
10
We have demonstrated the use of palladium catalyzed
addition of enolates to aryl bromides to synthesize
highly fiunctionalized benzyl amines and alcohols with
several points of potential diversity as intermediates
for further elaboration. Utilizing these catalyst systems,
we achieved good overall yields and increased reaction
rates. This coupling strategy combined with robust, well
established chemistries allowed us to efficiently synthe-
size the desired intermediates which we elaborated
further to synthesize drug-like molecules.
Scheme 6. Reagents and conditions: (a) Pd/C, H2, MeOH, 98% and
(b) 2-chloromethylpyridine HCl, acetone, 60 °C, 78%.
a large amount of the advanced intermediate 6 could
potentially be synthesized and used as the starting point
for a diverse set of substituted phenyl ethers. Indeed, 6
could be used as a common intermediate for the synthe-
sis of 4 (albeit with the SEM group instead of TBDPS)
and 5 as well as 10.
The conversion of 4–6, 8 and 10 to the corresponding
benzyl alcohols and the subsequent amines also pro-
ceeded smoothly (Scheme 7). Silyl deprotection, either
with HCl for the SEM group or TBAF for the TBDPS
group, gave benzyl alcohols 11a–e which were con-
verted to azides 12a–e using diphenylphosphoryl azide
(DPPA). The subsequent reduction of the azides with
References and notes
1. Conditions were used or modified from the following: (a)
Hofslokken, N. U.; Skattebol, L. Acta Chem. Scand. 1999,
53, 258; (b) Jung, M. E.; Lazarova, T. I. J. Org. Chem.
1997, 62, 1553; (c) Miyachi, H.; Nomura, M.; Tanase, T.;
Suzuki, M.; Muralami, K.; Awano, K. Bioorg. Med. Chem.
OR1
OR1
OR1
OR1
OR3
OH
N3
NH2
d
c
a or b
R2
4-6, 8, 10
R2
R2
R2
11
12
13
4: R1 = CH2(3-pyridyl), R2 = CO2CH3, R3 = TBDPS
5: R1 = CH3, R2 = CO2CH3, R3 = SEM
6: R1 = Bn, R2 = CO2CH3, R3 = SEM
11-13a: R1 = CH2(3-pyridyl), R2 = CO2CH3
11-13b: R1 = CH3, R2 = CO2CH3
11-13c: R1 = Bn, R2 = CO2CH3
8: R1 = CH3, R2 = CN, R3 = SEM
11-13d: R1 = CH3, R2 = CN
10: R1 = CH2(2-pyridyl), R2 = CO2CH3, R3 = SEM
11-13e: R1 = CH2(2-pyridyl), R2 = CO2CH3
Scheme 7. Reagents and conditions: (a) 5, 6, 8 and 10, HCl, 1,4-dioxane, 0 °C, 64–89%; (b) 4, TBAF, THF, 93%; (c) DPPA, DBU, 0 °C–rt and (d)
PPh3, 20:1 THF:H2O; 65–75% (two steps).
CH3
Br
N3
NH2
a
c
b
CO2CH3
CO2CH3
CO2CH3
CO2CH3
16
7
14
15
Scheme 8. Reagents and conditions: (a) NBS, Bz2O2, CCl4, 90 °C, 89%; (b) NaN3, DMF, 70 °C and (c) PPh3, 20:1 THF:H2O, rt, 82% (two steps).

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R. Shetty, K. K. Moffett / Tetrahedron Letters 47 (2006) 8021–8024
Lett. 2002, 12, 333; (d) Kraus, G. A.; Cui, W.; Seo, Y. Ho.
Tetrahedron Lett. 2002, 43, 7077.
toluene. The solution was stirred for 10 min and then added
to a stirred suspension of Pd(OAc)2, BINAP and the aryl
bromide (4.9 mmol) in 5.0 mL of toluene. The reaction
mixture was heated at 100 °C for 3 h, cooled to room
temperature, diluted with water and extracted with ether.
The organic layer was dried over anhydrous Na2SO4,
filtered, concentrated and the crude chromatographed on
silica gel using 10:1 hexanes:EtOAc to give 1.0 g of the
desired nitrile.
2. (a) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2002,
124, 9330; (b) Jørgensen, M.; Lee, S.; Liu, X.; Wolkowski,
J. P.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 12557.
3. Littke, A. F.; Dai, C.; Fu, G. C. J. Am. Chem. Soc. 2000,
122, 4020.
4. Isobutyronitrile (1.15 equiv) was added to a vial containing
a stirred solution of NaHMDS (1.3 equiv) in 5.0 mL of