Synthesis of ortho-substituted nitroaromatics via improved Negishi coupling conditions

Article abstract of DOI:10.1016/j.tetlet.2011.07.083

We describe modified Negishi coupling conditions that allow improved access to ortho-nitrophenylalanine derivatives. These useful amino acid intermediates can be further elaborated into biologically active lactams and cyclic hydroxamic acid targets.

Full text of DOI:10.1016/j.tetlet.2011.07.083

Tetrahedron Letters 52 (2011) 5211–5213
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of ortho-substituted nitroaromatics via improved Negishi
coupling conditions
⇑
Jamison B. Tuttle , Joseph M. Azzarelli, Bruce M. Bechle, Amy B. Dounay, Edelweiss Evrard, Xinmin Gan,
Somraj Ghosh, Jaclyn Henderson, Ji-Young Kim, Vinod D. Parikh, Patrick R. Verhoest
Neuroscience Medicinal Chemistry, Pfizer Worldwide Research & Development, Eastern Point Rd., Groton, Connecticut 06340, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
We describe modified Negishi coupling conditions that allow improved access to ortho-nitrophenylala-
nine derivatives. These useful amino acid intermediates can be further elaborated into biologically active
lactams and cyclic hydroxamic acid targets.
Received 22 June 2011
Revised 18 July 2011
Accepted 20 July 2011
Available online 4 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Negishi coupling
o-Nitroaromatics
Phenylalanine derivatives
Drug like structures
Scalable
Functionally diverse small molecules that have defined stereo-
centers are ubiquitous in the realm of biochemistry and drug dis-
covery. We are particularly interested in hydroxamic acids 1,
which have recently been disclosed as potential treatments for
neurological disorders1 or bacterial infections.2 The related carbo-
styril derivatives 2 have been evaluated as possible therapeutants
for diseases including diabetes,3 stroke,4 arthritis,5 heart disease,6
and as analgesics.7 Due to these potential applications, we sought
to develop a general route to a key intermediate that can access
both hydroxamic acid 1 and lactam 2. Synthesis of these structures
have been previously reported,8 but herein we describe an im-
proved and scalable sequence that utilizes a key Negishi reaction
to access a broad range of functionally diverse amino ester
derivatives.
Retrosynthetically, it was envisioned that Negishi coupling be-
tween a substituted o-nitroaromatic 4 and iodoserine derivative
5 would furnish the key phenylalanine intermediate 3 (Fig. 1), a
strategy inspired by Jackson’s pioneering efforts.9 At the time these
investigations were initiated, previous reports indicated that o-hal-
ogenated nitrobenzene derivatives coupled in low yields, typically
10–30%, and with variable reproducibility.10 One improvement to
this transformation, recently reported by the Jackson group uti-
lized Pd2(dba)3 and SPhos to couple 2-iodonitrobenzene in 66%
yield.11 To our knowledge, this is the only example of an improved
Negishi coupling on o-halonitrobenzenes. As the nitro group was
required for subsequent transformations, we sought to optimize
the Negishi conditions on these substrates and broaden the sub-
strate scope to include additional functional handles and groups
found in bioactive molecules. Herein, we describe the scope and
limitations of our studies.
In the initial optimization 2-iodonitrobenzene 6 was reacted
with the iodoserine derived zincate 7 generated using catalytic
iodine11,12 to provide the desired product 8 (Table 1). Coupling
using conditions reported by the Jackson group9 for 1 h provided
the desired material in low yield (entry 1, 7%). Using similar condi-
tions with lower catalyst and ligand loading, Jackson’s group had
reported a 28% yield of 8. A marked improvement was observed
by increasing the reaction time to 18 h (entry 2, 73%). In addition
to increasing the reaction time, alternative ligands13 were explored
in combination with Pd(OAc)2.13 In the event, use of Ruphos or
SPhos provided the desired product in good yields (entries 3–4,
85%). A slight improvement was found using XPhos (entry 5,
92%).14 Furthermore, a comparable yield was obtained despite
lowering the catalyst and ligand loading to 1 mol % and 2 mol %,
R2
N
R1
R1
R1
NO2
NHBoc
O
NO2 MeO
O
[H]
Negishi
+
X
X
NH2
CO2Me
NHP
1 R2 = OH
2 R2 = H
3
4
5
⇑
Corresponding author.
E-mail address: jamison.b.tuttle@pfizer.com (J.B. Tuttle).
Figure 1. A key Negishi coupling on o-nitrohalobenezene.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.083

5212
J. B. Tuttle et al. / Tetrahedron Letters 52 (2011) 5211–5213
Table 1
Table 2
Optimization of the Negishi coupling conditions
Nitrobenzene substrate scope
1 mol% Pd(OAc)2
2 mol% XPhos
1 M DMF, 16 h
NHBoc
CO2Me
NO2
NHBoc
NO2
Br
catalyst
ligand
DMF
IZn
1.25 eq.a
NHBoc
CO2Me
NO2
NHBoc
NO2
I
R
IZn
CO2Me
R
Yieldb (%)
CO2Me
Entry
Starting material
Product
6, 1.5 mmol
7
8
NO2
NO2
NHBoc
X = Cl, 87
X = I, 92
1
2
Entry Catalyst
(mol %)
Ligand
(mol %)
Time
(h)
Equiv
Yield
(%)b
X
zincatea
CO2Me
O
O
O
1
2
3
4
5
6
7
8
Pd2(dba)3(5)
P(o-tol)3(20)
P(o-tol)3(20)
RuPhos(10)
SPhos(10)
XPhos(10)
XPhos(2)
1
1.5
1.5
1.5
1.5
1.5
1.5
1.25
1.05
7c
NO2
NHBoc
NO2
Br
Pd2(dba)3(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(1)
Pd(OAc)2(1)
Pd(OAc)2(1)
18
18
18
18
18
18
18
73c
85
85
92
92
83
68
H
H
56
CO2Me
O
NO2
NHBoc
NO2
EtO
EtO
3
4
5
6
7
8
75
77
57
50
41
42
XPhos(2)
XPhos(2)
Br
CO2Me
a
b
c
F3C
NO2
NO2
NHBoc
Organozincate generated as a 1 M solution in DMF.
Isolated yields after silica gel chromatography.
Used TMSCI to activate the Zn to generate 7.
F3C
Br
CO2Me
F
F
NO2
NHBoc
NO2
respectively, (entry 6, 92%). The yield of this transformation di-
rectly correlated to the amount of zincate with higher loadings
providing increased yields (compare entries 6–8). Having opti-
mized these conditions, we sought to expand the substrate scope.
In order to broaden the substrate scope, a variety of o-nitrob-
romobenzenes were coupled using 1.25 equiv of the organozincate
with 1 mol % Pd(OAc)2 and 2 mol % XPhos (Table 2).15 In addition to
aryl bromides, suitably activated aryl chlorides coupled efficiently
under these optimized conditions (entry 1, X = Cl, 87%; X = I, 92%
yield). Consistent with the previous reports, a diverse number of
functional groups were tolerated even in the presence of an acti-
vating nitro group under these conditions. For example, aldehydes,
esters, and fluorides were coupled in good yields (Table 2, entries,
2–3 and 5–6) to provide useful functional group handles for further
diversification. Additionally, the tolerance of fluoro groups as well
as trifluoromethyl substituents allows access to pharmacologically
useful final products (Table 2, entries 4–6). Even sterically hin-
dered substrates coupled albeit in moderate yield (entry 7, 41%
vs entry 1, 92%). Regioselective coupling was achieved using 2-bro-
mo-5-chloronitrobenzene to provide the desired material in mod-
erate yield (Table 2, entry 8, 42%).
Br
CO2Me
NO2
NO2
NHBoc
F
Br
F
CO2Me
NO2
NO2
NHBoc
Br
CO2Me
Me
Me
Cl
NO2
Br
NO2
NHBoc
Cl
CO2Me
a
Organozincate generated as a 0.1 M solution in DMF.
Isolated yields.
b
Table 3
Bromonitropyridine substrate scope
1 mol% Pd(OAc)2
2 mol% XPhos
1 M DMF
NHBoc
NO2
NO2
NHBoc
IZn
N
CO2Me
N
1.25 eq.a
R
Br
CO2Me
R
Initial forays into Negishi couplings with related nitrobromo-
pyridines (Table 3) indicated that the coupling was less efficient
than for the aryl systems as has been reported for other bromopyri-
dines.16 For example, 3-bromo-2-nitropyridine and 3-bromo-5-flu-
oro-2-nitropyridine coupled with equal efficiency (entries 1 and 3).
The relative position of the nitrogen did not affect the yield in the
coupling (compare entries 2 and 3). Furthermore, coupling of 6-
methyl-5-fluoro-3-bromo-2-nitropyridine proceeded in a slightly
improved yield (Table 3, entry 4, 29%).
Entry
Starting material
Product
Yieldb (%)
N
NO2
NO2
N
NHBoc
1
2
3
4
22
Br
CO2Me
NO2
NO2
NHBoc
N
N
23
20
29
F
F
Br
F
CO2Me
N
N
NO2
NO2
N
N
Having demonstrated the scope of the improved Negishi cou-
pling conditions, the utility and practicality of this protocol for
multi-gram scale-up of hydroxamic acids 1 was assessed on a
NHBoc
Br
F
CO2Me
Me
NO2
NO2
Me
number of o-bromonitrobenzene targets. As
a representative
NHBoc
CO2Me
example, coupling of nitrobromide 8 on a 40 g scale afforded phen-
ylalanine derivative 9 in good yield (Fig. 2, 36 g, 63% yield).17 Sub-
sequent reductive cyclization using 5% Pt/C under H2 atmosphere
in pyridine, followed by removal of the Boc group furnished the de-
sired hydroxamic acid 10 in 47% yield over these two steps.18 This
scale-up sequence was effective for a broad range of substituted 2-
nitrohalobenzenes.
In summary, optimized conditions have been developed for a
Negishi cross coupling between an iodoserine derived zincate
and a broad range of functionally diverse 2-bromonitroaromatic
F
Br
F
a
Organozincate generated as a 1.0 M solution in DMF.
Isolated yields.
b
derivatives to furnish useful intermediates that provide access to
biologically active small molecules. These conditions have been
successfully utilized on a large scale to provide gram quantities
of trifluoromethoxy phenylalanine 9, an important intermediate

J. B. Tuttle et al. / Tetrahedron Letters 52 (2011) 5211–5213
5213
1.3 eq.
NHBoc
IZn
OMe
O
1) 5% Pt/C,
150 psi H2
pyr.
5 mol% Pd(OAc)2
10 mol% XPhos
OH
N
NO2
NHBoc
F3CO
O
F3CO
NO2
F3CO
DMF, RT
2) HCl IPA
NH2
Br
CO2Me
9, 36 g, 63% yield
8, 40 g
10, 24.8 g,
47% two steps
Figure 2. Utilizing the Negishi coupling as the key step in scale-up sequence.
associated exotherm. The solution was stirred until the exotherm subsided,
was cooled to room temp (ꢀ25 min) and was stirred until the iodoserine
disappeared as monitored by TLC. The zincate solution was syringed away
from the excess zinc and was added to a separate flask containing Pd(OAc)2
(4 mg, 0.018 mmol), X-Phos (15 mg, 0.032 mmol), and the aryl bromide
(1.88 mmol) in DMF (0.5 mL). The resulting mixture was stirred at room
temperature overnight. Upon completion as indicated by TLC, the reaction was
quenched with satd NH4Cl (10 mL), poured into H2O (50 mL) and extracted
with EtOAc (2 Â 50 mL). The organic layers were washed with H2O
(2 Â 100 mL), brine (1 Â 100 mL), dried over MgSO4, filtered, and
in the synthesis hydroxamic acid derivative 10. Future efforts will
focus on optimizing this chemistry for heterocyclic substrates.
Acknowledgments
We thank Professor Gregory Fu, Robert Singer, and Martin
Berliner for providing valuable insight on zinc activation methods.
We thank Professors E.J. Corey, Steven Ley, and Andrew Myers for
their insights into approaches for improving the pyridine coupling
conditions. Finally, we are very grateful to Donn Wishka and his
team of Peakdale scientists: Jessica Lyon, David Jones, Gemma
Turner, Nicola Solesbury, and Paul Beagley for their scale-up ef-
forts. Katherine Brighty is gratefully acknowledged for providing
useful feedback during manuscript revisions.
concentrated to
chromatography.
a crude oil. The desired material was isolated via flash
16. (a) Typical yields are low for Negishi couplings on pyridyl derivatives, see:
Zeng, Q.; Zhang, D.; Yao, G.; Wohlhieter, G. E.; Wang, X.; Rider, J.; Reichelt, A.;
Monenschein, H.; Hong, F.-T.; Falsey, J.R.; Dominguez, C.; Bourbeau, M. P.;
Allen, J. G. Preparation of heterocyclic compounds as protein kinase B (PKB)
modulators. WO20080716, 2009.; (b) Tabanella, S.; Valancogne, I.; Jackson, R.
F. W. Org. Biomol. Chem. 2003, 1, 4254–4261; (c) Walker, M. A.; Kaplita, K. P.;
Chen, T.; King, D. H. Synlett 1997, 2, 169–170.
17. Although 5 mol % Pd(OAc)2 and 10 mol % XPhos were used in the Negishi
coupling conditions, catalyst loadings of 1 and 2 mol %, respectively, have
comparable yields on related substrates.
References and notes
18. Degassed anhydrous DMF (42 mL) was added to zinc (13.72 g, 209.8 mmol)
under a flow of argon. Chlorotrimethylsilane (5.30 mL, 42.0 mmol) was added
and the mixture stirred vigorously for 30 min. Stirring was stopped and the
zinc was allowed to settle. The supernatant was decanted under a flow of argon
and the zinc washed with degassed DMF (2 Â 20 mL). A solution of Boc-3-
iodoalanine methyl ester (29.9 g, 90.9 mmol) in degassed DMF (75 mL) was
added to the zinc. Upon addition an exotherm was observed. The cloudy gray
solution was stirred for 30 min at room temperature and then the zinc was
allowed to settle. This was repeated for a second batch of zincate. The two
batches of zincate were combined by decanting the supernatant into a clean
flask under a flow of argon. A solution of bromide 8 (40.0 g, 140 mmol) in
degassed DMF (120 mL), palladium acetate (1.57 g, 6.99 mmol), and X-Phos
(6.67 g, 14.0 mmol) were added sequentially. The reaction was heated at 40 °C.
After 16 h the reaction mixture was poured into water (400 mL) and ethyl
acetate (250 mL) was added. The mixture was filtered through a pad of celite,
washing the filter cake with ethyl acetate (2 Â 50 mL). The layers were
separated, the aqueous extracted with ethyl acetate (100 mL) and the organics
combined. The organics were then washed with brine (5 Â 400 mL), dried
(MgSO4), and concentrated in vacuo. The resulting residue was purified by dry
flash chromatography (2% ethyl acetate in heptane to 20%) to give compound 9
as a brown solid (35.95 g, 63%).1H NMR (400 MHz, CDCl3): 7.84 (s, 1H), 7.47–
7.36 (m, 2H), 5.22–5.14 (m, 1H), 4.72–4.63 (m, 1H), 3.74 (s, 3H), 3.57 (dd, 1H),
1. Claffey, M. M.; Dounay, A. B.; Gan, X.; Hayward, M. M.; Rong, S.; Tuttle, J. B.;
Verhoest, P. R.. Preparation of bicyclic and tricyclic compounds as KAT II
inhibitors for treating cognitive and other disorders. WO 2010146488, 2010.
2. Davis, A. L.; Hulme, K. L.; Wilson, G. T.; McCord, T. J. Antimicrob. Agents
Chemother. 1978, 13, 542–544.
3. Sher, P. M.; Ellsworth, B. A. Triglyceride and triglyceride-like prodrugs of
glycogenphosphorylase inhibiting compounds. US 20040142938, 2004.
4. Patankar, S. J.; Jurs, P. C. J. Chem. Inf. Comput. Sci. 2002, 42, 1053–1068.
5. Sakamoto, M.; Takasu, H.; Motoyama, M.; Kyono, K.; Oota, K. Preparation of
carbostyril derivatives as extracellular matrix metal protease inhibitors. JP
08325232, 1996.
6. Kuhla, D. E.; Campbell, H. F.; Studt, W. L.; Molino, B. F. Bicyclic heteroaryl
thiazole compounds and their cardiotonic uses. WO 8603749, 1986.
7. Merz, H.; Banholzer, R.; Langbein, A.; Sobotta, R.; Stockhaus, K. Preparation of
3-methylamino-3,4-dihydrocarbostyrils and analogs as analgesic agents. DE
3823576, 1990.
8. McAllister, L. A.; Bechle, B. M.; Dounay, A. B.; Evrard, E.; Gan, X.; Ghosh, S.; Kim,
J.-Y.; Parikh, V. D.; Tuttle, J. B.; Verhoest, P. R. J. Org. Chem. 2011, 76, 3483–3497.
9. Jackson, R. F. W.; Wishart, N.; Wood, A.; James, K.; Wythes, M. J. J. Org. Chem.
1992, 57, 3397–3404.
10. (a) Jackson, R. F. W.; Moore, R. J.; Dexter, C. S. J. Org. Chem. 1998, 63, 7875–
7884; (b) Oswald, C. L.; Carrillo-Marquez, L. C.; Jackson, R. F. W. Tetrahedron
2008, 64, 681–687.
3.25–3.15 (m, 1H), 1.33 (s, 9H).
A mixture of compound 9 (72.18 g,
176.8 mmol) and 5% platinum on carbon (6.93 g added as a paste in water)
in pyridine (360 mL) in an autoclave was charged with hydrogen (150 PSI) and
stirred at rt. After 16 h, the mixture was filtered through a pad of Celite,
washing with ethyl acetate (270 mL). The combined filtrate and washings were
then concentrated in vacuo, azeotroped with heptane (3 Â 180 mL), and
triturated with 5% IPA in heptane (900 mL). The solids were then isolated by
filtration, washing with 5% IPA in heptane (300 mL), and dried at 50 °C to give
compound 10 as an off-white solid (36.7 g, 57%). 1H NMR (400 MHz, CDCl3):
8.46 (s, 1H), 7.23–7.17 (m, 2H), 6.93 (d 1H), 5.43–5.36 (m, 1H), 4.58–4.45 (m,
1H), 3.48–3.35 (m, 1H), 2.93–2.82 (m, 1H), 1.45 (s, 9H).LCMS (ES+): 99.53%,
[M+H] = 363.1.
Compound 9 (36.7 g, 101 mmol) was stirred in 3.8 M HCl in 1,4-dioxane
(395 mL) at rt for 6 h. The precipitate was isolated by filtration and slurried in
diethyl ether overnight. The precipitate was again isolated by filtration
washing with diethyl ether and dried in vacuo at 40 °C. Residual 1,4-dioxane
was removed by heating in HPLC grade methanol at reflux for 1 h (29.59 g in
150 mL), cooling to rt and filtering to isolate the solids, then drying in vacuo at
50 °C. This was done twice–once on the bulk and once on the concentrated
liquors to give in total compound 10 as a white solid (24.8 g, 82%).1H NMR
(400 MHz, D2O): 7.29–7.20 (m, 2H), 6.99 (d, 1H), 4.33 (dd, 1H), 3.24 (dd, 1H),
3.17–3.06 (m, 1H). LCMS (ES+): 99.80%, [M+H] = 263.05.
11. Concurrent to our studies reported herein, the Jackson group reported a similar
approach towards improving the Negishi coupling conditions with a variety of
aryl bromides: Ross, A. J.; Lang, H. L.; Jackson, R. F. W. J. Org. Chem 2010, 75,
245–248.
12. We have also used the TMSCl activation procedure reported by Jackson’s group.
For both methods, the organozincate solution was carefully syringed away
from excess zinc in order to avoid Zn(0) mediated reduction of the nitro group
to an amine.
13. For a recent review on monophosphine ligands, see: Surry, D. S.; Buchwald, S. L.
Chem. Sci. 2011, 2, 27.
14. Xphos: (a) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 6653–6655; Ruphos: (b) Milne, J. E.; Buchwald,
S. L. J. Am. Chem. Soc. 2004, 126, 13028; SPhos: (c) Walker, S. D.; Barder, T. E.;
Martinelli, J. R.; Buchwald, S. L. Angew. Chem., Int. Ed. 2004, 43, 1871.
15. General procedure: A 1 M stock of the zincate was prepared as follows: To a
suspension of zinc powder (196 mg, 2.0 equiv, based on the iodoserine, dried
under vacuum using a heat gun) was added DMF (0.7 mL) and catalytic iodine
(50 mg, 0.19 mmol). The reaction mixture turned from colorless to red to
colorless again in ꢀ2 min. After the return to colorless a DMF solution (1.9 mL)
of the iodoserine was added followed by additional iodine (50 mg). The
reaction turned from pale yellow to red, and back to colorless with an