Impact of lead impurities in zinc dust on the selective reduction of a dibromoimidazole derivative

Article abstract of DOI:10.1021/acs.oprd.6b00370

A low level of lead in zinc dust was identified as the causative agent responsible for inhibiting selective reduction of a dibromoimidazole derivative via metal agglomeration and lead deposition on the zinc surface.

Full text of DOI:10.1021/acs.oprd.6b00370

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Full Paper
Impact of Lead Impurities in Zinc Dust on the
Selective Reduction of a Di-Bromoimidazole Derivative
Jianguo Yin, Courtney K. Maguire, Nobuyoshi Yasuda, Andrew P. J. Brunskill, and Artis Klapars
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00370 • Publication Date (Web): 08 Dec 2016
Downloaded from http://pubs.acs.org on December 15, 2016
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Impact of Lead Impurities in Zinc Dust on the Selective Reduction of a Di-
Bromoimidazole Derivative
Jianguo Yin,* Courtney K. Maguire,* Nobuyoshi Yasuda, Andrew P. J. Brunskill and Artis
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Klapars
Department of Process Research & Development, Merck Research Laboratories, Rahway, New
Jersey 07065, USA
jianguo.yin@merck.com; courtney.west@merck.com
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
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TOC Graphic
Agglomerated Zn post rxn Zinc before (left) &
after (right) rxn
Bulk Zn
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Abstract:
A low level of lead in zinc dust was identified as the causative agent responsible for inhibiting
selective reduction of a di-bromoimidazole derivative via metal agglomeration and lead
deposition on the zinc surface.
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Keywords: Zinc reduction, metal contamination, Elbasvir, Zepatier, metal agglomeration
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Introduction
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Zinc is a versatile reagent in organic transformations. When used as a reducing agent, it is also
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often a favorite choice for the process chemist since it is readily available and inexpensive .
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However, trace amounts of other metal impurities, especially lead, in zinc can have a profound
impact on its reactivity. The improvement of reaction efficiency resulting from trace amounts of
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lead in zinc dust has been reported for a Wittig-type olefination using a zinc carbenoid , and for a
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thiocarbonyl reaction using zinc. However, lead as an impurity has been found to inhibit the
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Simmons-Smith cyclopropanation or the conversion of alkyliodides to alkylzinc reagents.
When the impact of metallic impurities on the reaction rate is negative, such impact can often be
overlooked, as diminished reactivity can usually be overcome through the use of excess reagent
with little impact to the cost of goods.
Elbasvir (1) is one of the active pharmaceutical ingredients in the once-daily HCV treatment
TM 6
Zepatier.
The synthesis of elbasvir required the use of N-Boc imidazole mono bromide 3 as a
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a-c
double Suzuki-Miyaura cross coupling partner to the boronate ester 2 (Scheme 1).
Scheme 1. Preparation of Elbasvir.
N
N
N
Boc HN
O
B
N
N
N
Br
H
3
O
O
O
O
N
N
H
O
B
O
N
N
NHCO Me
2
Ph
O
1
Ph
2
MeO CHN
2
Elbasvir
A cost-effective and reliable synthesis of the mono-bromide 3 is therefore important. As reported
previously, selective reduction of the N-Boc dibromo imidazole derivative 5 by zinc metal was
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c
developed as the enabling route to make this intermediate. During the course of process
development, it was discovered that a commercial supply of zinc dust was extraordinarily less
effective for the reduction reaction. The impact was initially ignored since the use of excess zinc
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could mitigate an incomplete conversion. Additional studies, discussed herein, identified the root
cause of low reactivity was trace lead content in zinc dust.
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Results and Discussion
The dibromide 5 was easily accessible through the bromination of N-Boc imidazole 4 as reported
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c
previously. Though a variety of methods for arylhalide reductions have been reported, the
primary focus was on the use of zinc dust in aqueous methanolic solution as these conditions
afford a cost-effective and practical system (Scheme 2). Initial optimization revealed a particular
sensitivity of the reaction to pH. In a reaction medium with pH values less than 8, unproductive
consumption of zinc metal was observed, presumably due to hydrogen gas generation. At pH
values greater than 10 a noticeably slower reaction was observed. The optimized reaction
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employed EDTA, ammonium hydroxide and zinc dust in a MeOH/water mixture at 40 C, which
maintained a pH of approximately 9. Under these conditions complete consumption of 5
occurred in 1.5 h using 1.3 equivalents of zinc, with formation of 5 mol % over-reduction
product 4. A simple extractive protocol was developed which rejected 4 to the aqueous phase
during workup, ultimately providing 3 in 86% yield and >99% purity.
Scheme 2. Optimized Reaction Conditions for Selective Reduction of Dibromide 5
MeOH/H O
N
N
2
N
Br
Br
N
+
N
N
N
N
N
1.2 equiv. EDTA
Boc
Boc
Boc
H
Br
H
4
H
2
.7 equiv. NH OH
4
5
3
1.3 equiv. Zn
o
3 : 4 = 94%: 5%
4
0 C, 1.5 h
When the optimized reaction conditions were employed using one of the commercial
sources of zinc dust, a severe retardation of the reaction rate occurred. Agglomeration of zinc
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metal occurred, and only 40% conversion was observed after a few hours using the optimized
zinc charge of 1.3 equivalents. The reaction could be pushed to completion, but only through
charging additional zinc (1.7 equiv. total) and buffer solution over a day. To determine the root
cause of this irreproducibility and devise a robust procedure for this transformation, a thorough
investigation was initiated.
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Various lots of zinc metal from multiple commercial suppliers were procured,
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characterized and evaluated for performance in the reduction reaction (Table 1). The results for
the zinc metal used in the initial optimization experiments (Zinc A) are shown in entry 1.
Additional lots of zinc from this supplier showed similar purity and specific surface area (SSA),
and performed well in the reduction reaction. The reaction gave greater than 95% conversion in
one hour. The effect of metal SSA on the reaction was evaluated (Table 1, Entry 4) and it was
found that even with a 34x decrease in SSA the reduction reaction was not impacted.
The zinc dust from the bulk supply (Zinc B) showed markedly different analytical results
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(
Table 1, Entry 5). The material displayed a significantly larger SSA (0.7513 m /g), and showed
high levels of trace metal impurities, including iron (920 ppm) and lead (2,390 ppm or 0.07
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mol% on the basis of zinc). These data suggested the sluggish reaction observed using the bulk
supply of zinc dust was due to the higher metal impurities, especially lead. A visual comparison
of the zinc dust before and after the reaction is shown in Figure 1, highlighting the agglomeration
that was observed.
Table 1: Analysis and Reactivity of Zinc Metal from Different Suppliers
*
Specific Surface
Zinc
Dust/Powder
Purity
(%)
Metal Impurities
(ppm)**
Reaction
Conversion (%)
Entries
Area (SSA)
#
2
(
m /g)**
Dust
Zinc A)
1
2
98
98
0.1960
Cu: 28
Cu: 35
>95
>95
(
Dust
0.2288
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Dust
98
0.2318
0.0068
Cu: 77; Fe: 32
Cu: 50
>95
>95
Powder
Dust
Zinc B)
99.9
Cu: 50; Fe: 920;
Pb: 2390
5
98
0.7513
37
(
#
#
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Powder
99.9
98
ND
ND
In: 40; Pb: 65
Pb: 10
84
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#
#
Dust
*
Purity as shown on vendor certificate of analysis; **Analytical data generated in this work; if an element is
#
not listed, the level was undetectable; The conversion of reduction reaction with 1.3 eq. of zinc after 1h at 40
o
##
C; Not determined
.
a)Zn dust before the reaction b)Agglomerated Zn residue c)Side by side comparison of
(
250X)
from the reaction (25X)
Zn dust before and after
reaction
Figure 1. a) SEM Images of zinc dust and b) agglomerated zinc; c) Visual comparison of zinc
dust and agglomerated zinc
In general, an empirical trend was noted between the level of trace metal impurities in the
bulk zinc, particularly lead, and conversion in the reduction reaction. Even high quality zinc
powder (99.9%) which contained only 65 ppm lead resulted in a lower conversion (entry 6).
Standard methods for activation of zero-valent metals (pre-treatment with acid or TMSCl) did
not return the reaction to typical conversion when trace metal impurities were present. Having
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ruled out zinc surface area and activation as root causes for poor performance in the reduction,
an investigation into the observed empirical correlation of trace metal impurities with low
reactivity was pursued.
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A series of spiking experiments using lead powder were performed (Table 2). The
control experiments using zinc A and B showed 100% and 50% conversion respectively as
expected after 3 h (entries 1 and 2). Addition of 9.1 wt% lead powder to zinc A led to only 30%
conversion after 3 h (entry 3) at which point the reaction was essentially stalled and metal
agglomerates were observed. Decreasing the lead amount 10 and 40 fold (corresponding to 0.91
wt% and 0.24 wt% of lead) resulted in improved but still incomplete conversions in both cases
(entries 4 and 5). Comparing the results in entry 2 and entry 5, the rate retardation observed by
addition of 0.24 wt% of lead powder to zinc A was much less severe than that observed using
zinc B containing the similar amount of lead. A probable cause is better dispersion of lead in zinc
B. Nevertheless, these spiking experiments clearly demonstrated that lead in zinc dust was likely
the root cause of the metal agglomeration and consequently lower conversion in the reduction
reaction.
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Table 2 Impact of Lead on Reaction Conversion
Reaction Conversion (%)
Entry
Lead added
Metal Residue
Filtrate
Zn dust
(wt %)
1
h
2h
3h
---
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Zn: 98%
Pb: 129 ppm
Zn: 2.7%
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2
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4
5
Zinc A
Zinc B
Zinc A
Zinc A
Zinc A
None
None
9.1%
95%
37%
28%
74%
89%
100%
Zn: 80%
Pb: 5.6%
Zn: 2.3%
Pb: 35 ppm
44%
29%
79%
92%
50%
30%
80%
93%
Zn: 89%;
Pb: 11%
Zn: 1.2%
Pb: 60 ppm
Zn: 96%
Pb: 3.9%
0.91%
0.24%
Zn: 2.3%
Zn: 2.5%
Zn: 98%;
Pb: 2.2%
It is hypothesized that due to the difference in oxidation potential between zero valent
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zinc and lead, only the former is competent to engage the imidazolyl bromide in a single
electron transfer reduction. As such, it was expected that after the reaction any recovered metal
should be enriched in lead, with the soluble zinc(II) by-product being removed to the solution
phase. Indeed this proved to be the case (Table 2), and for all reactions where lead was added, a
significant lead wt% enrichment in the recovered metal was found (entries 2-5). In order to
confirm lead was completely inactive in the reduction reaction, a separate reduction experiment
was carried out using 2.0 equiv. of lead powder (200 mesh, 99%) as the reducing agent. After the
o
reaction mixture was heated for 2 h at 40 C, no reaction was observed and 100% lead metal was
recovered. In addition, the lead powder quickly agglomerated, as is clear from a visual
comparison of the lead powder charged to and recovered from the reaction (Figure 2).
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a) Pb powder as received b) Pb agglomerates observed c) Side by side comparison
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under reaction conditions (25X) of Pb powder and Pb
agglomerates before and
after reaction
Figure 2 a) SEM image of Pb powder as received, b) SEM image Pb balls observed under
reaction conditions, and c) Visual comparison of Pb powder and Pb ball before and after reaction.
From the data collected it was clear that the formation of metal agglomerates was caused
by a higher lead content in the zinc dust. Despite the fact that the reduction reaction could
proceed using zinc of varied surface area (Table 1, entry 3 and 4), a drastic reduction in surface
area caused by agglomeration could still be the major reason for a stalled reaction by preventing
physical contact of zinc metal with the reaction medium. To further interrogate this hypothesis,
residual zinc isolated from experiment 3 in Table 2 was isolated, ground with a mortar and pestle,
and then returned to the reaction mixture and heated. This second reaction then proceeded
another 20%, after which the reaction again stalled and the zinc was visibly agglomerated.
Surface area is one of the critical attributes involved in the reaction and agglomeration of
metal particulates. To characterize the surface metal composition at the end of the reduction
reaction, X-ray Photoelectron Spectroscopy (XPS) analysis was performed (Table 3).
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Table 3 XPS Analyses of Zn Dust Surface Before and After the Reduction (weight %)
Entry
Sample
C
N
O
Zn
Br
0.0
0.1
Pb
ND
0.9
1
2
Zinc A
Zinc B
18.7
23.3
0.0
0.0
45.1
43.1
36.2
32.7
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Filtered residual metal
from Zinc A
Filtered residual metal
from Zinc B
3
4
30.5
46.2
6.2
8.5
37.7
30.6
24.2
11.2
1.1
2.4
0.3
1.2
The results suggest that coating of zinc metal surface by lead took place during the reaction. For
example, as shown in Table 4, the lead content on the surface of zinc B before the reaction was
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.7% on the basis of zinc (entry 2). When the reaction stalled, the residual metal was separated
from the reaction mixture and the weight of the recovered metal was reduced by about one third.
The Pb content on the recovered metal surface was only expected to increase proportionally.
However, the recovered metal residue from the reaction showed a surface lead content of 10.7%
on the basis of zinc, as shown in entry 4, conclusively demonstrating deposition of lead on the
alloy surface.
Table 4. Comparison of Surface Enriched Lead to Zinc Ratios Before and After Reaction
Entry
Lead/Zinc Ratio
Before Reaction
ND
Lead/Zinc Ratio
After Reaction
1.2%
Sample
1
2
Zinc A
Zinc B
2.7%
10.7%
Conclusion
In conclusion, this investigation demonstrated that lead impurities can have a significant impact
on the competence of single electron transfer processes that employ zero-valent zinc as the
terminal reductant in methanolic aqueous solutions. The findings suggest that lead contamination
of the Zn dust resulted in an enrichment of lead on the surface of the Zn dust, severe
agglomeration, and ultimately a stalled reaction. It is possible that this finding has relevance
beyond the zinc/lead mixture described herein, and given the prevalence of zero-valent metal
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reductions in the manufacture of commodity and fine chemicals, this study is expected to be
relevant to practicing synthetic chemists worldwide.
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Experimental Section
General Procedure for the Selective Reduction of Dibromoimidazole. To a solution of 5.0 g
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a
(
12.6 mmol) dibromoimidazole 5 in 20 ml of methanol and 5 ml of water was added 4.4 g
(15.1 mmol, 1.2 eq.) of ethylenediaminetetraacetic acid, 4.8 ml ammonium hydroxide solution
o
(~28%, 2.7 eq.) followed by 1.3 g zinc dust in one portion. The mixture was heated up to 40 C
and vigorously stirred for about 90 min or until the remaining 5 is less than 0.5 (area)% by
1
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HPLC normalized to the product 3. If necessary, additional small amount of zinc dust could be
charged to complete the reaction. The mixture was then filtered on a Buchner funnel and the
filtrate was mixed with 20 ml of brine and 35 ml of ethyl acetate. The organic layer separated
and the washed with 20 ml brine followed by 30 ml of 0.5% citric acid aqueous solution to
remove over reduced by-product 4. The solvent was then removed under vacuum on a rotovapor
o
o
at 50 C and residue dissolved in 20 ml of methanol at 50 C. After cooling the solution to room
temperature, 45 ml of water was added slowly over 3 hours. The resulting suspension was cooled
o
to 15 C and the product was collected by filtration on a Buchner funnel. The wet cake was dried
o
in a vacuum oven at 60 C to give 3.44 g (86%) white solids. All spectral data are consistent with
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a
those reported previously.
Specific Surface Area Measurement: Specific surface area measurements on samples are
carried out by nitrogen adsorption using the BET adsorption model. The instrument used is a
Micromeritics Gemini 2360 or equivalent nitrogen adsorption apparatus.
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X-Ray Photoelectron Spectroscopy Measurement: XPS data is quantified using relative
sensitivity factors and a model that assumes a homogeneous layer. The analysis volume is the
product of the analysis area (spot size or aperture size) and the depth of information.
Photoelectrons are generated within the X-ray penetration depth (typically many microns), but
only the photoelectrons within the top three photoelectron escape depths are detected. Escape
depths are on the order of 15-35 Å, which leads to an analysis depth of ~50-100 Å. Typically,
95% of the signal originates from within this depth.
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Acknowledgment
We acknowledge Jason Ash for conducting SSA analysis and collecting SEM images, and Aldo
Rancier for elemental analysis. We thank Benjamin D. Sherry, Narayan Variankaval, and Debra
Wallace for helpful discussion.
References
1. (a) Negishi, E. Organometallics in Organic Synthesis; Wiley: New York, 1980. (b) Knochel,
P.; Singer, R.D. Chem. Rev. 1993, 93, 2117.
2. Hudlicky, M. Reductions in Organic Synthesis; Wiley: New York, 1984.
3. Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem., 1994, 59, 2668.
4
. Hensen, M. M.; Grutsch, Jr. J. Organic Process Research & Development, 1997, 1, 168.
. Takai, K.; Kakiuchi, T.; Utimoto, K. J. org. Chem. 1994, 59, 2671
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. Coburn, C. A.; Meinke, P. T.; Chang, W.; Fandozzi, C. M.; Graham, D. J.; Hu, B.; Huang, Q.;
Kargman, S.; Kozlowski, J.; Liu, R.; McCauley, J. A.; Nomeir, A. A.; Soll, R. M.; Vacca, J. P.;
Wang, D.; Wu, H.; Zhong, B.; Olsen, D. B.; Ludmerer, S. W. Chem. Med. Chem., 2013, 8, 1930.
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7. (a) Mangion, I. K.; Chen, C.-y.; Li, H.; Maligres, P.; Chen, Y.; Christensen, M.; Cohen, R.;
Jeon, I.; Klapars, A.; Krska, S.; Nguyen, H.; Reamer, R. A.; Sherry, B. D.; Zavialov, I., Org.
Lett., 2014, 16, 2310. (b) Li, H.; Chen, C.-y.; Nguyen, H.; Cohen, R.; Maligres, P. E.; Yasuda,
N.; Mangion, I.; Zavialov, I.; Reibarkh, M.; Chung, J. Y. L., J. Org. Chem., 2014, 79, 8533. (c)
Li, H.; Belyk, K. M.; Yin, J.; Chen, Q.; Hyde, A.; Ji, Y.; Oliver, S.; Tudge, M. T.; Campeau, L.-
C.; Campos, K. R., J. Am. Chem. Soc., 2015, 137, 13728.
8
. Zinc dust /powder were purchased from following suppliers: entry 1 (Zinc A) through entry 4
from Aldrich, entry 1, 98%, <10 micron, lot SHBD6692V; entry 2, 98%,<10 micron, lot
8525KD; entry 3, 98% <10 micron, lot SHBC7595V; entry 4, 99.9%, 100 mesh, lot 01526BA;
entry 5 (Zinc B) from Alfa Aesar, 98%, <10 micron, lot DD131115-002; entry 6 from Alfa Aesar,
0
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9.9%, 140-325 mesh, lot J10Z045; entry 7 from Acros lot A0334048.
9
. According to footnote 9 in reference 3, the purity of commercially available zinc dust or zinc
powder is dependent on the smelting method. The zinc produced by pyrometallurgy (distilled
zinc) contains higher level of lead, ex. 0.07 mol% while zinc produced by hydrometallurgy
(
electrolytic zinc) was much purer (>99.9%) and it contains no lead.
10. Lead Powder (99% purity, 200 mesh) was purchased from Aldrich.
1. The oxidation potentials for zinc and lead are 0.762 V and 0.126 V respectively indicating
1
zinc is much easier to be oxidized than lead based on “General Chemistry” Chapter 15,
Oxidation-Reduction Reaction, Pauling L., Dover Publications, Inc., 1970.
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2. HPLC condition for the analysis of reduction mixture: Eclipse Plus C18 (50x4.6 mm, 1.8
o
um), column temperature at 40 C, 1.0 ml/min flow rate, UV detection at 210 nm wavelength, 5
ul injection volume; mobile phase A: 0.1% phosphoric in water; mobile phase B: acetonitrile;
Gradient program: initial 10% of B, increase to 90% of B at 15 min, total run time 15 min.;
Diluent: 10% of water in methanol; Sample preparation: Dissolve one drop of the reaction
mixture in 1 ml of the diluent.
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