Zn-mediated decarboxylative carbagermatranation of aliphatic: N -hydroxyphthalimide esters: Evidence for an alkylzinc intermediate

Article abstract of DOI:10.1039/c9sc04288a

Alkyl nucleophiles synthesized by decarboxylation of the corresponding N-hydroxyphthalimide esters (NHP esters) would inherit the complex structure of natural carboxylic acids and result in useful cross-coupling fragments. Herein, we report the synthesis

Full text of DOI:10.1039/c9sc04288a

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Zn-mediated decarboxylative carbagermatranation
of aliphatic N-hydroxyphthalimide esters: evidence
for an alkylzinc intermediate†
Cite this: Chem. Sci., 2020, 11, 488
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have been paid for by the Royal Society
of Chemistry
*
Wei-Tao Jiang, Shuo Yang, Meng-Yu Xu, Xiu-Ying Xie and Bin Xiao
Alkyl nucleophiles synthesized by decarboxylation of the corresponding N-hydroxyphthalimide esters (NHP
esters) would inherit the complex structure of natural carboxylic acids and result in useful cross-coupling
fragments. Herein, we report the synthesis of alkyl carbagermatranes via Zn-mediated decarboxylation of
NHP esters without Ni catalysis or photocatalysis. Mechanistic studies indicate that an alkyl zinc
intermediate was involved; however, the generation of alkyl zinc will be inhibited in the presence of Ni.
Hence, this study provides valuable resolution to the perplexing problem about whether organozinc was
involved in recently emerging catalytic systems of NHP ester–Zn. Meanwhile, alkyl zinc reagents from
NHP esters are compatible with aryl/alkyl bromides and iodides; therefore the scope of
carbagermatranation in this work precedes that of in situ-generated organozinc from alkyl halides.
Received 25th August 2019
Accepted 13th November 2019
DOI: 10.1039/c9sc04288a
rsc.li/chemical-science
superior cross-coupling reactivity but also promising orthogo-
nality with organoboron reagents, methods of the synthesis of
alkyl carbatranes are fewer than those of alkylboron.11 Hence,
expanding the library of alkyl carbatranes with a complex
structure is attractive to synthetic chemistry.
Herein, we reported a Zn-mediated decarboxylative carba-
germatranation reaction using aliphatic NHP esters as alkyl-
ation reagents (Scheme 1d). In this manner, we were able to
Introduction
In the realm of cross-coupling reactions, while the innovation of
catalytic systems has been occurring constantly, another major
concern should be the synthesis of nucleophiles. In recent
years, numerous methods have been extensively developed for
the synthesis of alkyl nucleophiles.1 In particular, synthesis of
alkyl nucleophiles by means of decarboxylation would help
incorporate complex structures that are derived from naturally
abundant carboxylic acid resources. Baran's group has already
reported the synthesis of diversied alkyl boronates via decar-
boxylation of aliphatic NHP esters under nickel or copper
catalysis (Scheme 1a).2 In addition, Aggarwal’s group and Li's
group also managed to synthesize alkyl boronates through
decarboxylation induced by light (Scheme 1a).3 By this strategy,
diversied alkyl silanes were also readily synthesized by Oes-
treich's group (Scheme 1b).4–6 It's noted that decarboxylative
functionalization has received increasing attention these years;7
decarboxylation for the synthesis of other kinds of nucleophiles
remains to be further explored.
Meanwhile, carbatranes of group 14 elements (Scheme 1c)
were proved to be efficient alkyl cross-coupling reagents back in
1992 and further demonstrated in recent years6c,8,9 (i.e. M ¼ Sn)
by Vedejs' and Biscoe's groups, respectively. Our group has
subsequently reported the synthesis of alkyl carbagermatranes
(i.e. M ¼ Ge)10 from in situ-generated alkyl Grignard reagents
and alkyl zinc reagents. While carbatranes exhibit not only
Department of Chemistry, University of Science and Technology of China, Hefei
230026, China. E-mail: binxiao@ustc.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9sc04288a
Scheme 1 Synthesis of alkyl nucleophiles by decarboxylation of the
corresponding NHP esters.
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Table 1 Condition optimizationa
Results and discussion
We envisaged that reductive cross-coupling of 1-bromo-
carbagermatranes (GeBr, 1) and aliphatic NHP esters would
be a feasible idea. However, when we conducted a blank control
experiment, in which only two starting reagents and Zn powder
were added, surprising results were obtained. Simply stirring
GeBr and n-butanoic acid NHP ester (2a) with Zn powder in
DMF at room temperature already gave n-propyl carbagerma-
trane (3a) in nearly quantitative yield (entry 1, Table 1). By
replacing Zn powder with other commonly used reductants in
the reductive cross-coupling reaction, such as Mg, Mn and
TDAE (tetrakis(dimethylamino)ethylene),12 no desired product
was detected (entry 2–4). Changing solvent to THF and DMAc
afforded 57% and 56% yield, respectively (entry 5 and 6).
Lowering the load of 2a resulted in lower yield (entry 7 and 8).
Then we applied the optimized condition for 2a to 2-methyl-
butyric acid NHP ester (2b), and only a trace amount of s-butyl
carbagermatrane (3b) was detected (entry 9). Increasing the
ꢀ
reaction temperature to 60 C would improve the yield to 32%
a
b
(entry 10). Swapping solvent to DMAc only gave 8% yield (entry
11). Nevertheless, using THF as solvent gave considerably
improved 68% yield (entry 12). In addition, extending the
reaction time to 18 hours made little difference in yield (entry
13). Ultimately, using 3.0 equivalent of Zn powder gave a satis-
factory yield of 80% (entry 14).
All reactions were performed on a 0.10 mmol scale. Determined by
NMR analysis with mesitylene as an internal standard.
acquire a wide range of alkyl carbagermatrane reagents and also
avoid the pre-preparation of alkyl halides. Furthermore, aryl/
alkyl halides were all well tolerated in this protocol. Above all,
it's proved that alkyl zinc was generated in the system, but only
in the absence of nickel.
With the optimal condition in hand, the scope of decar-
boxylative carbagermatranation was examined (Table 2).
Table 2 Scope of decarboxylative carbagermatranationa
a
All reactions were performed on a 0.1 mmol scale, and yields were determined by isolation unless otherwise noted. Method A: 1 (0.1 mmol), 2 (0.2
mmol), Zn powder (0.2 mmol), DMF (0.5 mL), RT, 12 hours. Method B: 1 (0.1 mmol), 2 (0.2 mmol), Zn powder (0.3 mmol), THF (0.5 mL), 60 ꢀC, 18
hours. b Conducted at 90 ꢀC instead.
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Table 3 Decarboxylative carbagermatranation of natural products and drugsa
a
All reactions were performed on a 0.1 mmol scale, and yields were determined by isolation unless otherwise noted. Method A: 1 (0.1 mmol), 2 (0.2
mmol), Zn powder (0.2 mmol), DMF (0.5 mL), RT, 12 hours. Method B: 1 (0.1 mmol), 2 (0.2 mmol), Zn powder (0.3 mmol), THF (0.5 mL), 60 ꢀC, 18
hours. 1.0 mL DMF was used as solvent instead. c 1H-NMR yield using mesitylene as an internal standard. 0.5 mL THF was used as solvent
b
d
instead. e Conducted at 60 ꢀC instead.
Conventional aliphatic NHP esters were successfully converted
We next investigate the mechanism of this strategy. Radical
to alkyl carbagermatranes with good to excellent yield (3c–h). opening along with the radical cyclization experiment was
Esters (3i–j), protected amine (3k) and boronate (3l) were also conducted (Scheme 2). Under the conditions of Method A, 2am
well tolerated in the system. Notably, unprotected terminal was converted to fully opening product 3f in nearly quantita-
alkynes did not interfere the reaction, and alkyne-containing tive yield, and 2an was converted to non-cyclization product
alkyl carbagermatrane (3m) was obtained in 65% yield. Chlo- 3an and cyclization product 3an0 with a ratio of 45 : 35. These
ride containing substrates were obtained in good yield (3n–o). experiments suggest that radicals were involved in the
We next examined the scope of secondary and tertiary reaction.
substrates.13 Isopropyl (3q) and hept-3-yl (3r) carbagermatranes
However, we still don't know whether radicals were directly
were readily synthesized in good to excellent yield. Secondary involved in the Ge–C bond formation step. Hence, more
benzyl carbagermatranes (3s and 3u) were also obtained in good evidence should be collected to gain clear insight into the
yield. In addition, cyclic strained products (3t and 3y) were mechanism. When TEMPO was added to the reaction (Scheme
successfully accessed.
3, upper), the TEMPO-captured product was detected in 14%
To further demonstrate the utility of this strategy, we applied GC yield, and no carbagermatranation product was detected.
it to drug and nature product-derived substrates and various
complex structures were successfully incorporated. Dehy-
drocholic acid NHP ester was converted to the corresponding
carbagermatrane (3aa) in 72% yield. Lithocholic acid and lino-
lenic acid-derived carbagermatranes (3ab and 3ae) were also
successfully accessed with the unprotected secondary alcohol
still remaining. However, for the case of 3ab, it was isolated in
an inseparable mixture of the corresponding carbagermatrane
and protonation byproduct with a NMR ratio of 2.1/1. All
primary and secondary benzyl carbagermatranes derived from
indomethacin (3ah), racemic ibuprofen (3af), ketoprofen (3ai)
and N-unprotected carprofen (3ag), were obtained in good to
excellent yield. Notably, racemization occurred when enantio-
merically pure naproxen was applied (3ai). At last, glutamic
acid-derived carbagermatrane (3al) was also obtained (Table 3).
Scheme 2 Radical probe experiments.
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rule out that radicals were involved in the Ge–C bond forma-
tion step.14
The above results indicated that interaction of NHP esters
and Zn might lead to the generation of alkyl zinc. It has been
a controversial issue in the regard of a recently popular NHP–
Zn–Ni system, namely whether alkyl zinc works as an inter-
mediate.15 To understand the behavior of radicals under
a
catalytic or non-catalytic system, we also conducted
a comparative experiment with or without a nickel catalyst.
When a nickel catalyst was added, a signicant amount of
alkyl homo-coupling product and a trace amount of alkyl
carbagermatrane were detected (Scheme 4). In the presence of
Ni, radicals are rather reduced by Ni than Zn. In contrast,
radicals are reduced by low valent Zn+ to carbanion in the
absence of Ni.15e,16 The distinct selectivity shown in Scheme 4
indicates that the organozinc intermediate may not be
involved in the NHP–Zn–Ni system.
To observe directly, 1H-NMR spectra of the alkyl zinc reagent
of our strategy and classic alkyl zinc regent were compared. 1H-
NMR spectra of both gave a set of clear signals of the ethyl group
(Scheme 5). The chemical shi of Zn-attaching CH2 was
approaching 0 ppm, which is in accordance with previous
reports.17 These highly matched spectra further support our
proposal that the alkyl zinc reagent was generated in situ via Zn-
mediated decarboxylation of aliphatic NHP esters.
To be distinguished from the synthesis of organozinc using
halides, Br/I-containing substrates were also tested (Scheme 6).
Primary and secondary bromide-containing carbagermatranes
(3ap–aq) were obtained in excellent yield. An iodide-containing
substrate was obtained in reasonable low yield (3ar). Mean-
while, aromatic bromide and iodide were all well compatible
(3as–au). These Br/I-containing carbagermatranes bear both
nucleophilic sites and electrophilic sites, which allow for
further diversied derivatizations. Indeed, selective Suzuki
cross-coupling took place using 3av (Scheme 6, under) as
a partner. Cross-coupling product 3aw was acquired in excellent
90% isolated yield, which means that the Ge–C bond was
perfectly preserved under Suzuki-reaction conditions and
reveals the orthogonality with other reactions of alkyl carba-
germatranes. Furthermore, intramolecular cyclization of 3av
was also conducted. By using iPr-Xuphos as the ligand,10 cycli-
zation product 4a was obtained in 70% yield. By simply swap-
ping the ligand with less hindered Me-Xuphos, a satisfactory
Scheme 3 Ruling out radical involvement in the Ge–C bond forma-
tion step.
Following this, 2a was stirred with equimolar Zn powder in
DMF at room temperature and Zn powder was almost dis-
solved in 12 hours to give a clear yellow solution, aer which
GeBr was added and further stirred for 12 hours to give
product 3a in 61% isolated yield (Scheme 3a, middle). It's
unlikely that radicals would survive for a very long time since
they tend to quench with each other or solvent aer they were
generated. Therefore, a more reliable experiment was con-
ducted. The clear solution was stirred for a very long time (i.e.
4 days) before being quenched by TEMPO, and then GeBr was
added (Scheme 3, under). Surprisingly, 3a was obtained in
a comparable yield of 55% (vs. 61%, Scheme 3, middle) and no
TEMPO-captured product was detected. The results clearly
Scheme 4 Interference experiment with the Ni catalyst.
1
Scheme 5 Comparison of H-NMR spectra of the alkyl zinc reagent of our strategy and classic alkyl zinc reagent.
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Notes and references
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Scheme
6 Br/I-containing substrates and orthogonal experiment
with Suzuki cross-coupling reaction. All reactions were performed on
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accessed through C–C bond cross-coupling before.
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Various alkyl carbagermatranes were synthesized via Zn-mediated
decarboxylation of aliphatic NHP esters, which enrich the cate-
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from natural carboxylic acid. It's proved that alkyl zinc reagents
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a simple system of aliphatic NHP esters and Zn powder. Mean-
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distinguished from alkyl halides, which was responsible for the
tolerance of aryl and alkyl halides. Our study provides more
insight into the decarboxylative chemistry of aliphatic NHP esters,
and the new generation of organozinc may have further applica-
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Conflicts of interest
The authors declare no competing interests.
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Acknowledgements
We thank the NSFC (21871239) and Youth Innovation Pro-
motion Association of the Chinese Academy of Sciences
(2015371) for nancial support.
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13 Tertiary and aryl substrates failed to give the corresponding
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14 The lack of reactivity of GeBr with radicals may be attributed
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