B. Results and Discussion
5. Summary and Outlook
The direct synthesis of polyfunctional indazoles has proven to be difficult so far, due to harsh reaction conditions precluding the presence of sensitive functions. However, the described method offers a concise route to such scaffolds. Since many functionalized indazoles display biological activity, further extensions might be directed to the preparation of various polyfunctional indazoles and their use as biologically active drugs.
5.2 Fischer Indole Synthesis using Functionalized Organozinc Reagents
We have described a new organometallic variation of the Fischer indole synthesis allowing the preparation of various polyfunctional indoles from readily available aryldiazonium tetrafluoroborates and functionalized primary and secondary alkylzinc halides. High regioselectivity in the indole ring formation was observed. This variation enhances the scope of the classical Fischer indole synthesis tolerating a broad range of functionalities and displaying a remarkable regioselectivity. As an application of this method, the antidepressant iprindole and the anti-inflammatory drug indomethacin were efficiently prepared.
Additionally, we have extended the scope and improved the reaction conditions for the preparation of polyfunctional indoles on a larger scale. In the course of our study, we have also developed an alternative preparation of indole derivatives via addition of alkenylmagensium or lithium reagents to azo compounds.
Scheme 83. Preparation of indomethacin and iprindole via addition of functionalized alkylzinc reagents to aryldiazonium salts.
The indole scaffold is present in many natural products. Since we have successfully developed and implemented a novel methodology to the synthesis of this scaffold, many indole-containing natural products might become available via organometallic total synthesis employing organozinc reagents.
5.3 Preparation of 1,3,5-Triazinylmagnesium Reagents via an I/Mg-exchange
We have developed a novel method for the preparation of stable 1,3,5-triazinylmagnesium reagents which readily react with aldehydes, acid chlorides and allylic halides furnishing a range of new functionalized fully-substituted 1,3,5-triazine derivatives.
Scheme 84. Preparation of a functionalized 1,3,5-triazinylmagnesium derivative followed by Cu-catalyzed allylation.
The facile preparation of functionalized triazinylmagnesium reagents offers a new access to a wide range of functionalization reactions. Thus, readily functionalized triazines are highly likely to find further applications in opto-electronic devices, due to their unique electronic properties.
5.4 Preparation of Functionalized organometallics via Direct Metal Insertion in the Presence of LiCl
We applied the direct Mg insertion in the presence of LiCl with and without in situ trapping with ZnCl2 towards the preparation of functionalized organometallic reagents leading to polyfunctional aromatics. Several sensitive functional groups are well tolerated by this method. Furthermore, we applied the direct zinc insertion for the preparation of substituted cycloalkylzinc reagents. Thereby, we investigated in detail the mechanism of a subsequent diastereoselective Csp3-Csp2 cross-coupling using DFT-methods and NMR-techniques. Via thermodynamical analysis of the organometallic intermediates, we developed a hypothesis for the origin of the high diastereoselectivities. This was best rationalized by assuming an
equilibration of the zinc reagents and the preferential formation of the most stable equatorial-Pd-intermediate, as supported not only by DFT-calculations, but also by NMR experiments.
Me ZnCl
H
Me H ZnCl
H H
Me
ZnCl H
X Pd L
Ar L Ar-X
Me PdL2Ar
H
Me
PdL2Ar H
H H
Me
Pd H
Ar L L
Me H
Ar
Me Ar
H PdL2
eq-Zn(tr ans) ax-Zn(cis) eq-Zn(cis)
f ast slow slow
transmetalation
reductive elimination X Pd
L Ar L
X Pd L
Ar L
eq-Pd(trans) ax-Pd(cis) eq-Pd(cis)
tr ans-product cis-product
Scheme 85. Mechanistic proposal for the diastereoselective Csp3-Csp2 cross-coupling of substituted reagents with aryl iodides.
Based on our proposed mechanism for the diastereoselective Csp3-Csp2 cross-coupling and its generality, further extensions might be focused on diastereoselective C-C bond formations of saturated heterocycles or particularly of natural products.
5.5 One-Step Synthesis of Functionalized Organoborates via Accelerated Direct Metal Insertion
Moreover, we have demonstrated an efficient and inexpensive one-step preparation of polyfunctional organoborates via an accelerated direct metal insertion tolerating a wide range of functional groups. The described method proved to be highly flexible and fast using a synergetic effect of B(OBu)3 and LiCl. Furthermore, we demonstrated the practicability of such polyfunctionalized organoborates in uncatalyzed addition reactions to aldehydes and in Suzuki-type cross-couplings.
Scheme 86. Preparation of a heteroarylborate via direct magnesium insertion in the presence of LiCl and B(OBu)3 and subsequent Suzuki-type cross-coupling with organic halides.
In addition, the substantial accelerating effect of B(OBu)3 has been demonstrated in the direct metal insertion with aryl bromides using less reactive metals, such as Al, Ca, and Zn.
Moreover, we showed that Li, K and Na are also feasible for the in situ preparation of organoborates via direct metal insertion.
This method is particularly interesting for the preparation of organoborates in industrial applications, since the direct magnesium insertion in the presence of borates and LiCl avoids expensive cryogenic techniques and toxic waste products. Furthermore, the compatibility of this method with sensitive functional groups is especially remarkable.
5.6 Highly Selective Metalations of Pyridines and Related Heterocycles Using New Frustrated Lewis Pairs
We have developed a new class of frustrated Lewis pairs based on BF3·OEt2 and LiCl-complexed Mg or Zn TMP-amides allowing an efficient, regioselective metalation of various N-heterocycles. This approach constitutes an expeditive preparation of versatile magnesium chloride heteroaryl trifluoroborates expanding the work of Molander et al. Furthermore, using DFT-calculations, we could theoretically rationalize the experimentally observed acceleration in the metalation reactions. The metalation of various N-heterocycles with or without BF3·OEt2 using hindered Mg-, Zn- or Al-bases allows a complementary regioselective functionalization leading to a range of new polyfunctional N-heterocycles.
BF3·OEt2(1.1 equiv)
N Ph
THF, 0 °C, 15 min
N Ph
BF3
N Ph
Mg B
F F F Cl THF
N Ph
CO2Et 1. TMPMgCl·LiCl
(1.1 equiv) -40 °C, 20 min 2. ZnCl2
-40 °C, 30 min 3. ArI, Pd cat.a
1. ZnCl2
-40 °C, 30 min 2. ArI,
Pd cat.a TMPMgCl·BF3·LiCl
(1.1 equiv)
84%
70%
THF, -40 °C, 10 min
Scheme 87. BF3-triggered accelerated metalations. ArI: p-IC6H4CO2Et ; [a] Pd cat.: [Pd(dba)2] (5 mol%);
P(2-furyl)3 (10 mol%), 40 to 25 °C, 12 h.
As we could demonstrate, the generated heteroarylborates constitute a new class of frustrated Lewis pairs with unexpected reactivities. Thus, these investigations offer access to novel accelerated metalation reactions and subsequent functionalization reactions. Hence, functionalization of versatile sensitive N-heterocycles have become readily available.
5.7 Direct Preparation of Functionalized Organoborates via Accelerated C-H Activation Using Novel Amidoborates
In summary, a new class of thermally stable frustrated Lewis pairs was developed and applied in the direct and accelerated synthesis of functionalized aryl and heteroarylborates via C-H activation. Furthermore, these organoboron reagents readily undergo uncatalyzed addition to aldehydes or Suzuki-type cross-coupling reactions.
Scheme 88. Direct preparation of organoborates followed by a Suzuki-type cross-coupling.
Furthermore, the development includes a modular concept allowing the preparation of versatile and custom-made amidoborate bases. Based on these developments, various inexpensive metal amide bases have become valuable in functionalization of substituted arenes and heteroarenes.
5.8 Highly Regioselective Preparation of Heteroarylmagnesium Reagents and Their Application in Functionalization and Regioregular Polymerization Reactions
In summary, we developed efficient Br/Mg-exchange reagents, such as 2,4,6-triisopropylphenylmagnesium bromide complexed by (Me2NCH2CH2)2O, for the highly regioselective preparation of five-membered heteroaromatics. Furthermore, we applied the generated heteroarylmagnesium reagents in selective mono- and bis-functionalization reactions.
S Me
Br Br S
Me
Br MgBr S
Me Br
CO2Et ZnCl2(1 equiv);
then Pd(PPh3)4 (4 mol%), THF, 25 °C, 1 h I
CO2Et MgBr·LiCl
iPr iPr iPr
(Me2NCH2CH2)2O THF, -20 °C, 16 h
86%
> 99:1
Scheme 89. Regioselective Br/Mg-exchange using ligand-complexed magnesium reagents followed by a Negishi cross-coupling.
In addition, we could achieve the regioregular polymerization of such organometallics leading to polymers and oligomers comprising 3-subtituted thiophene subunits using this methodology.
Ni(dppp)Cl2 (0.1 mol%)
50 °C, 24 h
Br S Br
N
Br S MgBr·LiCl N
S N S N
S N
Br H
15 Mw= 2464, PDI = 1.03 TIPMgBr·LiCl
(Me2NCH2CH2)2O THF, -20 °C, 16 h
(>99:1) 58% (rr >97%)
N N N N N
Hex Hex Hex Hex Hex
Scheme 90. Regioselective preparation of substituted thiophenylmagnesium reagents followed by Ni-catalyzed polymerization to the corresponding oligomers.
The described method proved to be general. Thus, full functionalization of five-membered heteroaromatics has become readily possible leading to novel polyfunctionalized heterocycles. Furthermore, as we could show, substituted regioregular polymers and oligomers of such scaffolds were prepared. Further extensions might include regioregular polymers with finely tuned electronic properties leading to functional materials for applications in organic photovoltaics.