Alkylation-Terminated Catellani Reactions Using Alkyl Carbagermatranes

Article abstract of DOI:10.1002/anie.202008482

The Catellani reaction has received substantial attention because it enables rapid multiple derivatization on aromatics. While using alkyl electrophiles to achieve ortho-alkylation was one of the earliest applications of the Catellani reaction, ipso-alkyl

Full text of DOI:10.1002/anie.202008482

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Accepted Article
Title: Alkylation-Terminated Catellani Reactions Using Alkyl
Carbagermatranes
Authors: Wei-Tao Jiang, Meng-Yu Xu, Shuo Yang, Xiu-Ying Xie, and
Bin Xiao
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10.1002/anie.202008482
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COMMUNICATION
Alkylation-Terminated Catellani Reactions Using Alkyl
Carbagermatranes
Wei-Tao Jiang, Meng-Yu Xu, Shuo Yang, Xiu-Ying Xie, and Bin Xiao*
[*]
W.-T. Jiang, M.-Y. Xu, S. Yang, X.-Y. Xie, Prof. Dr. B. Xiao
Department of Chemistry
University of Science and Technology of China
Hefei 230026 (China)
E-mail: binxiao@ustc.edu.cn:
Supporting information for this article is given via a link at the end of the document.
Abstract: Catellani reaction has received extensive attentions as it
allows rapid multiple derivatization on aromatics. While using alkyl
electrophiles to achieve ortho-alkylation is one of the earliest
features of Catellani reaction, beta-H incorporated ipso-alkylation
terminated reaction has not been realized to date. Herein, we report
alkylation
terminated
Catellani
reaction
using
alkyl
carbagermatranes (alkyl-Ge) as nucleophiles. Reactivity of alkyl-Ge
and alkyl-B(OH)2 in this reaction was also discussed. This reaction
realized efficient beta-H incorporated dialkylation, which is
inaccessible by Catellani reaction before.
Pd-catalyzed/NBE-mediated ortho-activation and ipso-
functionalization reaction, also known as Catellani reaction,[1,2]
features one of the most effective tools of constructing multiply
substituted aromatics. The most prominent advantage of this
type of reaction is that orthogonal combination of different ortho-
reactions and ipso-reactions (termination reactions) allows a
large number of difunctionalization patterns[3] (Scheme 1a). In
the past few decades, the scope of ortho-reactions has been
extended intensively from alkylation[1,4] to various recently
developed electrophiles (E-X).[5] Meanwhile, termination
reactions have been constantly emphasized throughout the
developing history of Catellani reaction. Taking representative
termination reactions as examples, Heck-type reaction was
firstly applied in 1997[1] and the most applied to date in the
termination event of Catellani reaction. Lautens elegantly
demonstrated that by combining with tandem cyclization
process,[6] Heck-type termination was successfully utilized in
multiple complex molecule synthesis, also in which phosphine
ligand was introduced for the first time providing more variables
for optimization. Subsequently, using aryl boronic acid as the
terminating reagent brought general method to the introduction
of aryl rings.[7] Next, introduction of alkynyl group at ipso position
was also realized using terminal alkynes.[8] A special type of
termination reaction would be ipso-hydrogenation obtaining
meta-substituted aromatic rings.[9] In 2015, by combining
directed C-H activation with Pd/NBE catalysis, Yu and Dong
independently realized meta C-H functionalization using NBE
derivatives as transient mediator.[10] In addition, heteroatom-
introducing termination has also enriched the content of
Catellani reaction.[11] In particular, introduction of boron as a
special heteroatom granted the potential of further
functionalizations that might be inaccessible by direct
termination.[12] Nevertheless, direct alkylating[13] termination by
general alkyl nucleophiles[14] (especially the ones with beta-H)
has not been reported yet.
Scheme 1. Alkyl nucleophiles in Catellani reactions
While many challenges of Catellani reaction have been
addressed, alkylation-terminated variants remain a challenge.
We assume that the difficulties of alkylation terminated Catellani
reaction probably stem from the requirement of transmetalation
of alkyl group on the bulky 2,6-disubstituted Aryl-Pd(II)
intermediate. For instance, Suzuki reaction, which has been
remarkably successful regarding cross-coupling, however was
less efficient (e.g. comparing to Heck type termination) in
termination step of Catellani reaction. In fact, in the report by
Catellani
of
ortho-alkylation/ipso-Suzuki-terminated
difunctionalization, ortho-substituted aryl boronic acid was
unsuccessful substrate,[7,15] suggesting that the efficiency of
termination step is sensitive to the properties and structure of
the nucleophiles. It is noted that, in 2005, Lautens’ group
discovered that the use of alkyl boronic acids in Catellani
reaction would end up with ipso hydrogenated products
(Scheme 1b).[9] It is noteworthy that modification of NBE[3b] has
enabled
significant challenges such as ortho mono-
functionalization of haloarenes[16] to be overcome in the Catellani
reaction. However, we assumed that such strategy may not
significantly benefit ipso-alkylation since transmetalation takes
place after the extrusion of NBE. Therefore, modification of
alkylating reagents themselves would be a more practical
strategy to realize ipso-alkylation terminated reaction.
Recently, organogermanium nucleophiles[17-18] have
received increasing attentions due to their balanced reactivity
and stability in cross-coupling and environmentally friendliness.
We found out that alkyl carbagermatranes (alkyl-Ge) were
capable of realizing transmetalation with high efficiency.[17a]
Hence, we envisioned that using alkyl-Ge as ipso-terminating
1
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reagents would help overcome the aforementioned challenges.
We began with a classic model Catellani reaction using aryl
iodide 1a, alkyl iodide 2a and beta-H containing alkyl-Ge 3a
aiming at realizing ortho/ipso-dialkylation of aryl ring. Meanwhile
alkyl-B(OH)2 was also tested for comparison.[19]
improve the yield while PdBr2 was able to give satisfying 85%
yield (Entry 8). In addition, some NBE derivatives[21] were also
evaluated yet did not prevail over the simplest NBE (Entry 9-13).
With the optimized reaction condition in hand, the scope of
ipso/ortho-dialkylation protocol was investigated. We first
examined the scope of aryl iodides (Figure 1A). Electron-rich 1-
iodo-2-methoxybenzene, 1-Iodonaphthalene and 1-iodo-2,3-
dimethylbenzene were smoothly converted to dialkylation
products with good yields (4b-d). Meanwhile, electron-poor aryl
iodides gave lower yields (4j, 4k). Pyridine ring (4f) was
compatible to give 74% yield. Tert-butyldimethylsilyl-protected
benzyl alcohol (4e) and trifluoromethoxyl group (4g) were also
tolerated in moderate yield. Not only Cl-bearing aryl ring (4h),
but also Br-bearing one (4i) was successfully tolerated. It’s
noted that by subjecting ortho unsubstituted 1-ethyl-4-
iodobenzene (1l), Et-I and alkyl-Ge 2a to the standard condition,
48% yield of trialkylation product 4l was obtained with 44% 2a
Table 1. Reaction conditions optimization[a]
n
unreacted. Efficiency dropped dramatically with nPr-I and Bu-I
used as ortho alkylating reagents, suggesting that steric
hindrance of Ar-Pd(II) species has certain impact on the
transmetalationof the final alkylating termination step,[22] which is
in line with Catellani’s finding.[7, 23] Following, the scope of alkyl
iodides was inspected (Figure 1B). 1-iodo-4-phenyl-butane and
even longer 1-iodododecane were readily converted to
dialkylation product with excellent yields (4o-p). Protected
alcohol (4q), alkene (4r), ester (4s) and ketone (4u) were
tolerated to give good yields. Notably, unprotected alcohol was
also compatible albeit giving a lower yield (4t). It’s noteworthy
that while 1-chloro-4-(3-iodopropoxy)benzene was converted to
dialkylation product in 73% yield (4v), its bromide analog gave
slightly lower 62% yield. In addition, amide-containing (4w-x)
alkyl iodides was also tolerated. With respect of the scope of
alkyl-Ge, a variety of funtionalized alkyl-Ge were tested (Figure
1C). Ethyl, benzyl and 3-phenylpropanyl-Ge were converted to
dialkylation products with good yields (4y-aa). Acetal (4ab),
ester (4ae) and amide-containing (4af) alkyl-Ge were also
proved to be excellent ipso terminating partners. Notably, 4ac
and 4ad were readily obtained in good yields with Cl or Br atom
preserved. We next investigated the tolerance of boron-
containing substrates (Figure 1D). To our surprise, even in the
presence of Cs2CO3, a commonly used base for Suzuki cross-
coupling reactions, not only boronic acid pinacol ester (Bpin), but
naked boronic acids were well tolerated to give boron-contaning
dialkylation products in moderate to good yields (4ag-an).
[a] Yields were determined by GC analysis using nhexadecane as internal
standard. Reaction conditions: 0.1 mmol 1a, 0.1 mmol 2a, 0.2 mmol 3a, 0.005
mmol [Pd], 0.01 mmol ligand, 0.2 mmol N, 0.2 mmol Cs2CO3, 0.5 mL CH3CN,
100 oC, 14 hours. Yield of using nhexyl-B(OH)2 instead of nhexyl-Ge was given
in the parenthesis.
Initially we tried the reaction conditions of Lautens’,[9] and
ipso-hydrogenation terminated product 4a’’ was the major one
along with target dialkylation product 4a as minor one (15% for
alkyl-Ge and 10% for alkyl-B(OH)2, Entry 1, Table 1). We
proposed that ligand effect would have predominant impact on
the alkylation at ipso position. Therefore, a few electron-deficient
ligands were screened. Indeed, for the case of alkyl-Ge, the
yield of 4a was improved remarkably using L2 and L3 (Entry 2-
3), which were less effective in direct cross-coupling reaction of
alkyl-Ge.[17a] Especially, 4a was obtained in 75% yield with ipso
hydrogenated product 4a’’ greatly suppressed using L3. L4[17a]
and L5[20], which were proved efficient in alkyl carbatranes
cross-coupling reactions, however, barely gave any dialkylation
To demonstrate the utility of this alkylation terminated
protocol, modification of drugs and natural products derivatives
was performed (Figure 2). Vitamin E and estrone-derived aryl
iodides were converted successfully to 4ao and 4as with 61%
and 77% yields respectively. Jasmonic acid (4ap), indomethacin
(4aq) and linoleic acid-derived alkyl-Ge[24] (4ar) were also
competent terminating partners giving corresponding modified
drug and natural products with good yields. At last, fructose-
derived alkyl iodide was able to give dialkylation product 4at in
65% yield.
n
products (Entry 4-5), suggesting that the presence of bulky Bu
group at ortho position before the transmetalation of alkyl-Ge
should be credited for. As for the case of alkyl-B(OH)2, L2-L5
failed to improve the yield of 4a and 4a’’ was still found to be the
major product. With the optimal ligand L3 found, more conditions
were tested using alkyl-Ge. Changing Pd source also helped
2
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Figure 1. Scope of aryl iodides, alkyl iodides, alkyl-Ge and boron-containing substrates. Yields were determined by isolation unless otherwise noted. Reaction
conditions: 0.1 mmol aryl iodides 1, 0.1 mmol alkyl-Ge 2, 0.2 mmol alkyl electrophiles 3, 0.005 mmol PdBr2, 0.01 mmol L3, 0.2 mmol NBE, 0.2 mmol Cs2CO3, 0.5
mL CH3CN, 100 oC, 14 hours. [a] Yields were determined by GC analysis using nhexadecane as internal standard, 4.0 equivalent of alkyl electrophiles was used.
[b] trace product was detected by TLC, 4.0 equivalent of alkyl electrophiles was used.
Figure 3. Intramolecular cyclization. Yields were determined by isolation.
Reaction conditions: 0.1 mmol 5, 0.2 mmol 3b, 0.005 mmol PdBr2, 0.01 mmol
L3, 0.2 mmol NBE, 0.2 mmol Cs2CO3, 0.5 mL CH3CN, 100 oC, 14 hours.
Figure 2. Modification of drugs and natural products derivatives. Yields were
determined by isolation. Reaction conditions: 0.1 mmol aryl iodides 1, 0.1
mmol alkyl-Ge 2, 0.2 mmol alkyl electrophiles 3, 0.005 mmol PdBr2, 0.01 mmol
L3, 0.2 mmol NBE, 0.2 mmol Cs2CO3, 0.5 mL CH3CN, 100 oC, 14 hours.
We previously established a method to synthesize aryl
iodide-incorporated alkyl-Ge through decarboxylative
carbagermatranation,[24] which enables us to realize
intramolecular dialkylation Catellani reaction (Figure 3). With an
array of precursor 5 in hand, intramolecular cyclization was
performed. 6a and 6b were obtained in good yields while
3
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10.1002/anie.202008482
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medium ring 6c and 6d shown no difference in yields in general.
Noticeable decline in yield was observed when the size of ring
was increased to 10/11-member (6e-f) or even larger (6g). It
needs to be pointed out that all intramolecular cyclization was
performed in standard condition without diluted (0.2 M),
suggesting the high efficiency of alkyl-Ge as ipso terminating
reagents.
but already proved effectively feasible by Corey’s group.[30]
Theoretically, dialkylation product could be obtained by
hydrogenation of Heck-terminated Catellani products. However,
no Heck-type terminated Catellani reaction using propylene as
terminating reagents was reported by far. Most of all, C-C
double bond in homogeranyl group (7) may not survive from the
subsequent hydrogenation..
In addition, it was found that aryl electrophiles also worked
well for ortho-arylation in this protocol. Ortho-arylation/ipso-
alkylation products were obtained with moderate to good yields
(Figure 4), which further expands the paradigm of this method.
Scheme 3. Simplified synthesis of bioactive molecule. Reaction conditions:
step 1: 0.1 mmol 1b, 0.1 mmol 2n, 0.2 mmol 3u, 0.005 mmol PdBr2, 0.01
mmol L3, 0.2 mmol NBE, 0.2 mmol Cs2CO3, 0.5 mL CH3CN, 100 oC, 14 hours;
step 2: i) 0.14 mmol 7, 0.14 mmol TiCl4, 0.6 mL DCM, RT, 2 days; ii) 0.3 mmol
BBr3, RT, 2 hours. Yields were determined by isolation.
In conclusion, dialkylation of aromatic rings was realized
by Pd/NBE cooperative catalysis using alkyl carbagermatranes
as alkylation terminating reagents. The scope of aryl iodides,
alkyl/aryl halides and alkyl carbagermatranes were investigated.
This protocol of dialkylation was compatible with alkyl boronic
acid and able to construct medium rings by intramolecular
cyclization. Its practicability was further demonstrated by
modification of drugs and natural products derivatives and the
simplified synthesis of bioactive molecule. Our study extends the
scope of Catellani reaction to a new dimension with alkylating
termination, and mechanism study is helpful for inspiring further
exploitation of using other alky nucleophiles in Catellani
reactions.
Figure 4. Scope of ortho-arylation. Yields were determined by isolation.
Reaction conditions: 0.1 mmol aryl iodides 1, 0.1 mmol alkyl-Ge 2, 0.2 mmol
aryl electrophiles 3, 0.005 mmol PdBr2, 0.01 mmol L3, 0.2 mmol NBE, 0.2
mmol Cs2CO3, 0.5 mL CH3CN, 100 oC, 14 hours.
Regarding the aspect of mechanism, Deuterium label
experiments were performed. Both paralleled and competitive
deuterium label experiment gave low KIE value (see SI, Scheme
S1-S2), suggesting that ortho C-H activation was partially
included in rate-determining step, which agreed with previous
researches.[19b, 25] Monitoring of reaction progress revealed that
transmentalation of alkyl nucleophiles is crucial to this
dialkylation strategy and also elxpained why alkyl-Ge worked
better that alkyl boronic acids (see more dicussion in SI, Section
5).[26]
Acknowledgements
We thank Prof. Zhen-Hua Gu and Prof. Qing-Xiang Guo for
helpful discussion, and the National Key R&D Program of China
(2017YFA0700104), NSFC (21871239), Fundamental Research
Funds for the Central Universities (WK2060190081) and Youth
Innovation Promotion Association of the Chinese Academy of
Sciences (Y201987) for financial support.
At last, Catellani reaction has unique advantage in the
synthesis of complex molecule, and we believe our dialkylation
protocol will bring more convenience to the synthesis. Totarol is
a natural terpene isolated from Podocarpus totara of New
Zealand that exhibit antibacterial activity. Previous studies reveal
that altering substituent at ortho position to OH group in Totarol
helps regulate its lipophilicity without compromising its
antibacterial activity.[27] However, previous methods for the
synthesis of its derivatives are tedious. By our protocol,
Conflict of interest
precursor polyenes
7
was synthesized from 1-iodo-2-
n
methoxybenzene, Pr-Ge and homogeranyl iodide[28] 3u in one
step (Scheme 3). Following TiCl4-mediated polycyclization[29]
and demethylation by BBr3 was able to give nPr analog of
Totarol 8 in 41% yield. The NMR data of analog 8 is consistent
with reported literature.[27] and our synthetic route is much more
simplified. Limited by the commercial source of SbCl5 and the
ligand, enantioselective polycyclization of 7 was not performed
The authors declare no conflict of interest.
Keywords: Catellani reaction • Carbagermatrane • ipso-
alkylation • Organogermanium
4
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i
[22] Combination of PrGe, various aryl iodides and alkyl halides were tried,
i
they failed to realize transmetalation and PrGe was fully recovered,
which also proves the sensitivity of steric hindrance in termination step.
5
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Entry for the Table of Contents
Alkylation-terminated Catellani reaction has not been well-executed in a very long time mainly due to the significant challenge of
the transmetalation of beta-H incorporated alkyl groups onto the steric hindered aryl-Pd(II) intermediate. Herein, this challenge is
overcome by using highly efficient alkyl-Ge nucleophiles as terminating reagents.
6
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