A novel iodide-catalyzed reduction of nitroarenes and aryl ketones with H3PO2 or H3PO3: Its application to the synthesis of a potential anticancer agent

Article abstract of DOI:10.1021/ol102174w

A novel iodide-catalyzed reduction method using hypophosphorous and/or phosphorus acids was developed to reduce both diaryl ketones and nitroarenes chemoselectively in the presence of chloro and bromo substituents in high yield. This efficient and practical method has been successfully applied to a large scale production of a potential anticancer agent

Full text of DOI:10.1021/ol102174w

ORGANIC
LETTERS
2
011
Vol. 13, No. 19
220–5223
A Novel Iodide-Catalyzed Reduction of
Nitroarenes and Aryl Ketones with H PO
5
3
2
or H PO : Its Application to the Synthesis
3
3
of a Potential Anticancer Agent
George G. Wu,* Frank X. Chen, Danny LaFrance, Zhijian Liu, Scott G. Greene,
Yee-Shing Wong, and Ji Xie
Department of Process Chemistry, Merck Research Laboratories, P.O. Box 2000, 126
East Lincoln Avenue, Rahway, New Jersey 07065, United States
george.wu@merck.com
Received August 3, 2011
ABSTRACT
A novel iodide-catalyzed reduction method using hypophosphorous and/or phosphorus acids was developed to reduce both diaryl ketones and
nitroarenes chemoselectively in the presence of chloro and bromo substituents in high yield. This efficient and practical method has been
successfully applied to a large scale production of a potential anticancer agent.
In the synthesis of a potential anticancer agent, Lona-
farnib, we needed to reduce both a nitro group and an
aromatic ketone in the presence of chloro and bromo
subsituents on aromatic rings as shown in Scheme 1.
A number of methods including hydrogenation, mod-
ified hydrides, metals or metal derivatives (Sn, SnX2,
TiCl , Zn), sulfides (Na S, Na S O ), and enzymes are
of active pharmaceutical ingredients. Various methods
have been developed to reduce nitro and ketone groups
2
while minimizing the undesired dehalogenation, but most
of the reported methods have limited scope and/or utilize
3
complex procedures. Furthermore, bromo and iodo sub-
4
stituents do not survive those conditions. Recently, this
group has reported a novel ZnX -modulated Pd/C and
2
3
2
2
2
4
known to reduce nitro groups to the corresponding
Pt/C method for chemoselective hydrogenation and hy-
drogenolysis of halogen-substituted nitroarenes, alkenes,
1
amines. The first three methods (hydrogenation, hy-
drides, and metals) are also capable of reducing ketones
5
benzyl ethers, and aromatic ketones. However, these
1
to the CH group under certain conditions. However,
b
procedures only reduce an aromatic ketone to its corre-
sponding alcohol and not to the desired methylene group.
We now report a novel iodide-catalyzed chemoselective
reduction of nitroarenes to anilines and diaryl ketones to
2
most of the methods also reduce bromo and chloro sub-
stituents, thus generating dehalogenated impurities. On an
industrial scale, it can be extremely difficult to separate
relatively small amounts of dehalogenated impurities from
the desired product to meet the strict purity requirements
(
3) (a) Kosak, J. R. Ann. N.Y. Acad. Sci. 1970, 172, 175. (b) Kosak,
J. R. In Catalysis of Organic Synthesis, Vol. 1; Jones, W. H., Ed.;
Academic Press: New York, 1980; p 107. (c) Baumeister, P.; Blaser,
H. U.; Scherrer, W. Stud. Surf. Sci. Catal. 1991, 59, 321. (d) Yang, X.;
Liu, H. Appl. Catal. 1997, 164, 197.
(4) (a) Pacoe, W. Catal. Org. React. 1998, 18, 121. (b) Wilkison, H. S.;
Tanoury, G. J.; Wald, S. A.; Senanayake, C. H. Tetrahedron Lett. 2001,
42, 167. (c) Huang, Y.; Liao, P.; Zhang, Y.; Wang, Y. Synth. Commun.
1997, 27, 1059.
(
1) (a) Larock, R. C. Comprehensive Organic Transformations,
John Wiley & Sons: New York, 1999; Chapter 7, pp 821ꢀ827. (b) For ketone
reduction, see ref 1a, pp 61ꢀ64.
(
2) (a) Mallat, T.; Baiker, A. Appl. Catal., A 2000, 200, 3 and
references cited therein. (b) Baumeister, P.; Studer, M.; Roessler, F. In
Handbook of Heterogeneous Catalysis, Vol. 5; Ertl, G., Knzinger, H.,
Weitkamp, J., Eds.; VCH: Weinheim, 1997; p 2186. (c) Straz, A. M. In
Catalysis of Organic Reactions; Kosak, J. R., Ed.; Marcel Dekker: New
York, 1984; p 335.
(5) (a) Wu, G.; Huang, M.; Richards, M.; Poirier, M.; Wen, X.;
Draper, R. W. Synthesis 2003, 11, 1657. (b) Wu, G.; Tormos, W. J. Org.
Chem. 1997, 62, 6412.
1
0.1021/ol102174w r 2011 American Chemical Society
Published on Web 08/26/2011

methylene groups using either hypophosphorous acid or a
combination of hypophosphorous and phosphorus acids.
Furthermore, we report a successful application of this
novel method to the synthesis of an arylhalogen-contain-
ing anticancer agent, Lonafarnib.
studies to optimize the reaction conditions to minimize the
byproduct and improve the operability on a large scale. A
numberofexperimentswere carried out, and the results are
listed in Table 1.
As indicated by entry 2 of Table 1, reducing the amount
of H PO and replacing HI with NaI did not reduce the
3
2
level of the byproduct. Use of less potent reducing agents
such as H PO (entry 3) or NaH PO (entry 4) in the
3
3
2
3
Scheme 1. Proposed Synthesis of Lonafarnib
presence of 2 equiv of NaI and aqueous HBr completed
thereduction witha longerreaction time. However, neither
of the conditions prevented the formation of the iodo
byproduct. We thought that the level of the iodo displace-
ment byproduct should be proportional to the concentra-
tionofiodide and thatthe less the iodide concentration, the
lower the byproduct. To our delight, reducing the amount
of NaI from 2 to 0.1 equiv suppressed the formation of the
byproduct to an undetectable level. However, use of a
catalytic amount of NaI (0.1 equiv) also slowed the desired
reductions. For example, use of 3.5 equiv of H PO and
3
2
0.1 equiv of NaI (entry 5) completely reduced the diaryl
ketone, but only partially reduced the nitro group. On the
other hand, a mixture of 8 equiv of H PO and 0.1 equiv of
3
3
NaI (entry 6) reduced the nitro group quickly, but the
carbonyl group very slowly. Concentrated HCl was not
tested in this study.
Recently, Fry reported a chemoselective reduction of
aryl ketones in the presence of bromo substituents with
6
a combination of H PO and I in refluxing HOAc. This
3
2
2
method is safer than a previously reported procedure
7
using red phosphorus and HI under refluxing conditions.
However, similar conditions are not known to reduce
9
nitroarenes. Thus, we initially planned a two-stage reduc-
a
Table 1. A Novel Reduction of Nitroarenes and Aryl Ketones
tion: first reducing the aryl ketone with the H PO -based
3
2
method and then the nitro group with our ZnX -modu-
2
5
lated Pd/C catalyst. In light of safety considerations, we
focused our effort on H PO -based reducing agents, rather
3
2
than the red phosphorus. To our suprise, the first reaction
with 11 equiv of H PO and 4 equiv of HI in refluxing
3
2
water not only reduced the ketone group to a methylene
group but also reduced the nitro group to the correspond-
ing aniline; both the bromo and chloro substituents were
largly preserved. To the best of our knowledge, this is the
first example of nitroarene reduction with the HIꢀH PO
3
2
system. This method can be complementary to the current
methods such as hydrogenation, hydride, and metal-based
procedures. However, there were two issues associated
with this procedure: (1) a major byproduct was observed
at about the 5% level; and (2) a severe foaming at the
beginning of the reduction. The byproduct was identified
as the 3-iodo analogue of 2, apparently derived from an
iodo replacement of the 3-bromo substituent on the pyr-
idine ring, and was very difficult to remove to a pharma-
ceutically acceptable level. Thus, we undertook additional
reducing
agents
(equiv)
catalyst
entry
(equiv) solvents 2:2-iodo comments
1
2
3
4
5
6
7
H
3
PO
2
(11)
HI (4)
H
2
O
95:5
Complete
Complete
Complete
Complete
H PO (3.5) Nal (2) HBr/H O 95:5
3
2
2
2
2
2
2
2
H
3
PO
3
(8)
Nal (2) HBr/H
O
O
O
O
O
95:5
95:5
NaH
2
PO
2
(11) Nal (2) HBr/H
H
H
H
H
3
PO
3
PO
3
PO
3
PO
2
3
2
3
(3.5) Nal (0.1) HBr/H
100:0 Nitro remain
100:0 Ketone remain
100:0 Complete
(8)
Nal (0.1) HBr/H
Nal (0.1) HBr/H
(2)/
(3.5)
a
All reactions were carried out at 115 °C for 1 to 16 h.
(
6) (a) Hicks, L.; Han, J. K.; Fry, A. J. Tetrahedron Lett. 2000, 41,
817. (b) Gordon, P. E.; Fry, A. L. Tetrahedron Lett. 2001, 42, 831.
7) (a) Bradsher, C. K.; Vingiello, F. A. J. Org. Chem. 1948, 13, 786.
b) Lee, W.; Park, C. J. Org. Chem. 1993, 59, 7149.
7
(
Although the foaming was manageable on laboratory
scales byadjusting both the agitation and the addition rate,
itwould not be easytooperate inplantproduction. Careful
observations indicated that the severe foaming takes place
only at the beginning of the reaction. We speculated that a
(
(8) Blatt, A. H.; Gross, N. J. Org. Chem. 1957, 22, 1046.
(9) (a) Wu, G. G.; Wong, Y.; Poirier, M. Org. Lett. 1999, 1, 745.
(
b) Bernard, C. F.; Casey, M.; Chen, F. X.; Grogan, D. C.; Poirier, M.;
Williams, R. P.; Wong, Y.; Wu, G. U.S. Patent 6,495,689, December 17,
002.
2
Org. Lett., Vol. 13, No. 19, 2011
5221

fast initial reaction rate with H PO may account for the
3
conditions, nitro ketone 1 was converted to 2, which was
directly brominated to give dibromo 4 in one pot in 93%
overall isolated yield. Afterward, the amino group in
compound 4 was removed under standard conditions with
NaNO and H PO in H SO in 82% isolated yield. The
2
foaming and use of a less potent reducing reagent such as
H PO couldreduce the foaming. Indeed, replacingH PO
with H PO did minimize the foaming at the beginning of
3
3
3
2
3
3
the reduction. Based on this observation and the results
from entries 5 and 6 in Table 1, we decided to do a
sequential reduction of the nitro group first and then the
aryl ketone group by using a stepwise addition of H PO
2
3
2
2
4
introduction of the doubly benzylic chiral center was
previously reported in 95% ee using a chiral alkylation
1
method with LDA and quinine. The ee was further
1
3
3
and H PO . Thus, nitro ketone 1 was first treated with
3
enhanced to 99% through a salt formation with N-acet-
2
1
1
H PO and 0.1 equiv of NaI in aqueous HBr at 115 °C to
yl-L-phenylalanine. With these achievements, we have
accomplished an efficient and practical synthesis of
Lonafarnib.
3
3
reduce the nitro group followed by an addition of H PO
3
2
to reduce the carbonyl group. As shown by entry 7 in
Table 1, this combination method gave a complete reduc-
tion of both the nitro and the ketone groups while mini-
mizing the iodo byproduct to below the detection limit
(0.03%). In addition, operational hazardous evaluation
indicated that this procedure is suitable for production.
a
Table 2. Reduction of Nitroarenes
Scheme 2. An Efficient Synthesis of Lonafarnib
a
3 3
Conditions: reactions were carried out with 4 equiv of H PO and 2
equiv of NaI in aqueous HBr and HOAc at 115 °C.
We have applied this method to the synthesis of Lona-
farnib shown in Scheme 2, which we have performed on a
Next, we subjected a number of nitroarenes to this novel
reducing method, and our results are summarized in Table
2. In all 8 entries, the nitro goup was completely reduced to
the corresponding anilines in 83 to 98% isolated yields.
The chemoselectivity for the chloro nitroarenes is excellent
as shown by substrates 1 and 8. On the other hand, the
chemoselectivity is good for meta-substituted bromo
9
00 kg scale. Thus, nitration of tricyclic compound 3 with
1
HNO and H SO gave nitro ketone 1 as a mixture of two
regioisomers (7-nitro and 9-nitro) in a 3:7 ratio and 98%
3
2
4
1
isolated yield. Under the newly discovered reduction
0
(10) Chen, F. X.; Wong, Y.; Eckert, J. M.; Liang, F,; Zou, N.;
Kim-Meade, A. S.; Poirer, M.; Thiruvengadam,, T. K.; Wu, G. G. U.S.
Patent 7,049,440, May 23, 2006.
(11) Kuo, S. C.; Chen, F. X.; Hou, D.; Kim-Meade, A.; Bernard, C.;
Liu, J.; Levy, S.; Wu, G. G. J. Org. Chem. 2003, 68, 4984.
5
222
Org. Lett., Vol. 13, No. 19, 2011

nitroarenes such as substrates 1, 18, and 20, but poor for
other substrates (10 and 12). This method is not chemose-
lective for iodonitroarene (13). Apparently, additional
studies are required to understand the chemoselectivity
better.
adjustment in workup. It is worth noting that use of more
potent red phosphorus and HBr has been shown to reduce
benzophenonechemoselectively inthe presence of a bromo
7
group. In addition, use of iodine as a catalyst instead of
6
NaI effectively reduces diaryl ketones.
Fry has postulated a mechanism for the reduction of aryl
6
ketones with HI, H PO , and refluxing HOAc. HI was
3
2
speculated to be the direct reducing agent for the carbonyl
þ
Table 3. Reduction of Aryl Ketones and Nitroarenes
group to give CH and one “I ” species, which combines
2
ꢀ
with “I ” to produce iodine. Iodine is then reduced by
H PO back to HI in the presence of acid. Similarly, we
3
2
speculated a two-stage process for the reduction of the
nitro group. NaI reacts with HBr to produce a small
amount of HI. HI reduces ArꢀNO first to ArꢀNO and
2
then quickly to ArNH . Both H PO and H PO can
2
3
2
3
3
reduce iodine back to HI. In both reductions, H PO or
3
2
H PO is the ultimate reducing agent.
3
3
In summary, we have discovered a novel and practical
iodo-catalyzed reduction of nitroarenes with H PO or
H PO . This method can reduce some aryl ketone groups
3
2
3
3
in the presence of chloro and bromo substituents. It can be
complementary to the current reduction methods includ-
ing hydrogenation, hydrides, and metal reagents. Further-
more, we have successfully applied this method to the
synthesis of a potential anticancer agent.
Acknowledgment. We thank Dr. David Tschaen,
Mr. Marc Poirier, and the plant staff for their support
(all Merck). We also thank Drs. David Hughes, Ingrid
Mergelsberg, and Steve Miller (all Merck) for their review
of the manuscript.
Finally, we studied the reduction of those substrates
bearing aryl ketones or bifunctional groups, and our
results are summarized in Table 3. As discussed earlier, a
combination of H PO and H PO in the presence of 0.1
Supporting Information Available.
Experimental
13
1
procedures, full characterization data, and H and
2
1
C
3
3
3
2
NMR spectra for all compounds. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
equiv of NaI effectively reduced both the diaryl ketone and
the nitro groups in nitro ketone 1 (entry 1). For the rest of
the substrates in Table 3, only H PO along with 2 equiv of
(12) Representative Experimental Procedure: To a 1-L three-necked
flask equipped with a mechanical stirrer, a thermometer, and a con-
3
2
NaI was used since the foaming was manageable on
laboratory scales. As indicated by entries 2 and 3, this
procedure reduced substrates 22 and 24 in 90% and 92%
isolated yields, respectively. However, it only reduced the
nitro group in the less activated substrates (26, 28). Ap-
parently, the electon-withdrawing pyridine ring in sub-
strates 1, 22, and 24 played a role in the reduction of the
diaryl ketone group. The lower recovery yield in entry 5
was due to an intermolecular imine formation during pH
denser were charged, under nitrogen, 50 g (0.14 mol) of nitro ketone 1, 2
3 3
g of NaI (13.3 mmol), 45 g of H PO (0.55 mol), 250 mL of hydrobromic
acid (48%), and 50 mL of water. The resulting suspension was heated to
about 115 °C and stirred at this temperature for 4 h. The reaction
mixture was cooled to 60 °C, and 40 mL (0.30 mol) of 50% H PO were
3
2
added. The reaction mixture was heated to 115 °C for another 6 h. After
cooling to 20 °C, the reaction mixture was transferred into a solution of
2
00 mL of ammonium hydroxide and 100 mL of MeOH. The pH was
adjusted to 5 with ammonium hydroxide, and the resulting suspension
was stirred for 1 h. The solid was filtered, washedwith water, and dried at
60 °C to give 46.9 g (99% yield) of 2 as a mixture of 7- and 9-amino
isomers.
Org. Lett., Vol. 13, No. 19, 2011
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