sp3 Cross-Coupling - American Chemical Society

Subscriber access provided by IDAHO STATE UNIV

Article

Alkyl Carbagermatranes Enable Practical Palladium-Catalyzed sp2-sp3 Cross-Coupling Meng-Yu Xu, Wei-Tao Jiang, Ying Li, Qing-Hao Xu, Qiao-Lan Zhou, Shuo Yang, and Bin Xiao J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b02776 • Publication Date (Web): 18 Apr 2019 Downloaded from http://pubs.acs.org on April 18, 2019

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

Alkyl Carbagermatranes Enable Practical Palladium-Catalyzed sp2sp3 Cross-Coupling Meng-Yu Xu, Wei-Tao Jiang, Ying Li, Qing-Hao Xu, Qiao-Lan Zhou, Shuo Yang and Bin Xiao* Department of Chemistry, University of Science and Technology of China, Hefei 230026, China. Supporting Information ABSTRACT: Pd-catalyzed cross-coupling reactions have achieved tremendous accomplishments in the past decades. However, C(sp3)-hybridized nucleophiles generally remain as challenging coupling partners due to their sluggish transmetalation compared to the C(sp2)-hybridized counterparts. While single-electron transfer-based strategy using C(sp3)-hybridized nucleophiles had made significant progress recently, less breakthroughs have been made concerning traditional two-electron mechanism involving C(sp3)-hybridized nucleophiles. In this report, we present a series of unique alkyl carbagermatranes that were proven to be highly reactive in cross-coupling reactions with our newly developed electron-deficient phosphine ligands. Generally, secondary alkyl carbagermatranes show slightly lower, yet comparable activity with its Sn analogue. Meanwhile, primary alkyl carbagermatranes exhibit high activity and they were also proved stable enough to be compatible with various reactions. Chiral secondary benzyl carbagermatrane gave the coupling product under base/additive-free conditions with its configuration fully inversed, suggesting that transmetalation was carried out in an “SE2(open) Inv” pathway, which is consistent with Hiyama’s previous observation. Notably, the crosscoupling of primary alkyl carbagermatranes could be performed under base/additive-free conditions with excellent functional group tolerance and therefore may have potentially important applications such as stapled peptides synthesis.

1. INTRODUCTION Over the past several decades, Pd-catalyzed crosscoupling reactions have changed organic synthesis significantly along with marvelous development of nucleophiles1, among which cross-coupling reactions accomplished by alkyl nucleophiles2 appear to be more challenging ones. In recent years, single-electron transmetalation process has made remarkable achievements mainly due to the realization of the transmetalation of some challenging stable alkyl nucleophiles like trifluoroborates and silicates3. Notably, in many cases, the radical and two-electron transmetalation processes are mutually orthogonal on the account of regioselectivity, functional group tolerance and stereo-control4, etc. Hence, two-electron transmetalation is still worthy of further exploration. Two-electron transmetalation can be deemed as the attack of an alkyl carbanion toward an electron-deficient Pd center, therefore for some nucleophiles such as alkyllithiums5, alkylmagnesiums6 or alkylzincs7, higher transmetalation activity suggests stronger Lewis basicity8. Such nucleophiles usually exhibit sensitivity toward air, water or some specific functional groups. On the contrary, air-stable nucleophiles such as alkylboranes9 and alkylsilicons10 usually require extra base (or F-) to promote two-electron transmetalation. However, the addition of additives usually complicates the system, and

then compromises the functional group tolerance of Pdcatalyzed reactions, which could have been more appealing. Figure 1. Cross-coupling of group nucleophiles and history of carbatranes. M

Open-chain alkyl nucleophiles: M(alkyl)4 or alkyl-MX3

N

Atranes:

Si

Hiyama:

OH Si(alkyl)3

Ge

not reported

Sn

many examples R

Aryl-Hal M

R

cat. Pd, Ligand

Related work

M

R

Sn

1o alkyl

Biscoe, 2013

Sn

2o alkyl

Ge

allyl, phenyl, alkenyl, and alkynyl but fail in alkyl

This work: Ge

Alkyl-Hal Br

Mg or Zn

N

Aryl-Hal cat. Pd, Ligand Ge

alkyl

alkyl-SiF3

Vedejs, 1992

Kosugi, 1996

N

14

Alkyl

Alkyl

80 - 120 oC

* Previously difficult to obtain pure "Ge-Hal" * Synthesis of Ge-Alkyl from "in situ" generated alkyl metal reagents * Successful cross-coupling of alkyl germanium nucleophiles * Excellent functional group tolerance under base/additive-free condition

ACS Paragon Plus Environment

Journal of the American Chemical Society 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

We sought inspiration through analyzing the nature of the developed nucleophiles in history, and group 1411,12 alkyl nucleophiles interest us the most. For Si-containing nucleophiles, the pioneering work by Hiyama and coworkers has successfully demonstrated that primary and benzyl secondary alkyl(trifluoro)silanes exhibit activity for Pd-catalyzed sp2-sp3 cross-coupling13. A series of unique trialkyl[2-(hydroxymethyl)phenyl]silane derivatives have further achieved transmetalation of nonactivated secondary alkyl group such as iPr, cyclopentyl and cyclohexyl group14. On the other hand, considerably plenty of cross-coupling examples of using Sn-containing nucleophiles including various open-chain alkyl tin reagents, some of which even exhibit additive-free transmetalation ability15, were presented. Particularly, alkylcarbastannatranes, initially used in cross-coupling by Vedejs16, have elegantly solved the selectivity problem of four alkyl substituents on the Sn center during the transmetalation process. Moreover, transannular coordination of carbastannatranes guarantees them greater transmetalation ability17. Remarkably, Biscoe recently expanded their cross-coupling to secondary alkyl carbastannatranes, and more importantly, demonstrated that enantioenriched secondary alkylcarbastannatranes undergo transmetalation via a stereospecific retention mechanism18. Our group has focused on using Ge19,20 reagent for cross-coupling, naturally, carbagermatranes (abbreviated as Ge in following text) came across our mind. Actually, to our knowledge, all kinds of atrane-like and open-chain alkyl germanium reagents failed to realize successful cross-coupling reactions for neither primary nor secondary alkyl groups. 11, 21

Page 2 of 8

Figure 2. Synthesis of alkyl carbagermatranes from alkyl halides. N

+

Alkyl Hal

Ge

Mg or Zn powder

Ge-Br N

N

Ge

Ge a3: 76%

N

O

N Ge

Ge

O

Ge

N O

a7: 88%b

Ge

N

Bpin

a8: 87%b Bpin

Ge

a9: 88%b

N

Bpin

N

NHBoc

COOBn

Ge

b

N

NHCbz

Ge

b

a12: 86% 99.6% e.e.

Ge

Si

a11: 98%a

a10: 76%b

COOMe Ge

Alkyl

N

O a6: 92%a

N

Ge

n a4: n=0, 91%a a a5: n=1, 92%

b

a1: n=2, 95% a2: n=0, 94%a

N

Si

4 a

Ge

N

O

n

N

N

60 oC, 8 h Up to 95%

Br

COOAllyl NHFmoc

a14: 83%b 99.6% e.e.

a13: 85% 99.9% e.e. Ph

N

N

Ge

a15: 75%c

N

Ge

F

Ge

Ge

a16: 90%a

a17: 81%b

Isolated yield. a Hal = Br, Mg powder, THF. b Hal = I, Zn powder, DMF. c Hal = Cl, Mg powder, THF. See SI for details.

Figure 3. Ligands screening. N

Pd(dba)2 2 mol% L 6 mol%

Br +

Ge

n

Hex

o

MeCN, 120 C, 16 h

a1

2. RESULTS AND DISCUSSION

b1

CF3

In light of the above, we first attempted to synthesize Ge-Cl on the basis of the reported literature21, which was found to be ambiguous and resulted in an inseparable mixture of Ge-Cl and Cp2ZrCl2. However, after the mixture was worked up with inexpensive benzylmagnesium chloride, Ge-Bn was readily separated (see SI for details). Further work-up with Br2 afforded pure Ge-Br, which represents the first example of the synthesis of Ge-Br compounds. We proposed that using Ge-Br would change the fact that alkyl carbagermatranes can only be synthesized from pre-prepared alkyllithiums or alkylmagnesium. Fortunately, one-pot reaction of GeBr with in situ generated alkyl Grignard or alkylzinc reagents gave desired alkyl carbagermatranes smoothly (Figure 2). Especially with alkylzinc reagents, the alkylGe bearing various functional groups can be readily obtained. Meanwhile, decades’ development of phosphine ligands gives us more inspiration. Generally, electron-deficient phosphine ligands promote the transmetalation of Stille reactions15, which was also observed in Biscoe’s work (i.e. JackiePhos)18. Nevertheless, when we applied JackiePhos in our reaction, it only gave 17% yield (Figure 3, L1). The

N

OMe Cy P Cy i Pr

OMe P

MeO R1

i

R1

CF3

F3C

R2

CF3 F3C

MeO i Pr

CF3

CF3

L1 R1 = R2 = Pr (JackiePhos) 17% yield L2 R1 = NMe2; R2 = H 33% yield L3 R1 = Oi Pr; R2 = H 42% yield

CF3

CF3

Cy

P Cy

P F3C

CF3

CF3

F3C

P

Ph2P

i Pr BrettPhos L4 3% yield

P

F3C

CF3

Fe

Fe

F3C

CF3 L5 48% yield

L6 11% yield

CF3

L7 38% yield

F3C For b1-b5:

CF3 P R1

R1 CF3 R2 n

40% yield CF3 L8 R1 = R2 = Me L9 R1 = OMe; R2 = H 36% yield i L10 R1 = R2 = Pr 98% yield 95% yield (100 oC) 75% yield (80 oC) n

Hex O2N

NC b2: 97%a

n

Hex

Hex

N

Ge

Br

78-85% Recovery from reaction mixture

MeOOC

O

n

Hex

MeO b3: 95%a

b4: 96%a

b5: 90%a

Standard condition: 1.0 equiv. Ar-Br, 1.2 equiv. a1, 2 mol% Pd(dba)2, 6 mol% Ligand L10, 0.2 M MeCN, 120 oC, 16 h. a Isolated yield.

2 ACS Paragon Plus Environment

Page 3 of 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society including the fusion of di[3,5-bis(trifluoromethyl)phenylphosphino] group. Inspired by that, we combined aryl-substituted indenyl skeleton with di[3,5bis(trifluoromethyl)phenylphosphino] group and L8-L10 were successfully synthesized. When L10 was applied in the reaction, a nearly quantitative yield was achieved. Lowering the temperature still offered satisfying yields (95 % at 100 oC, 75% at 80 oC). Then we preliminarily tried some cross-coupling reactions between nhexyl-Ge and aryl bromides, and all afforded alkylation products (b2-b5) with excellent yields (>90%).23,24 It is noteworthy that no additive or base was used in the reaction16, and Ge-Br could be recovered by crystallization in 78-85% yield. The NMR spectrum of synthesized GeBr and recovered GeBr in CD2Cl2 are in accordance with each other.

result indicated the challenge we encountered when Sn was replaced by Ge. Further screening of ligands (L2-L7) suggested that di[3,5-bis(trifluoromethyl)phenylphosphino] group in the ligand is necessary for the reaction, and electron-rich phosphine ligands (L4, L6) would diminish the yield. Specifically, we noticed that the most sterically hindered ligand L1 showed the worst performance among the three ligands L1-L3. This trend led to the speculation that proper modification on the skeleton of JackiePhos analogs to reduce the steric hindrance would be promising. Yu, etc. reported the synthesis of a series of Buchwald-type ligands containing aryl-substituted indenyl skeleton22 which may reduce the steric hindrance by elongating the distance between phosphorus atom and its adjacent aryl plane, however not Figure 4. Substrates scope of the cross-coupling reactions. N

MeOOC

OHC

b6: 99% (95%a)

MeO

O

b7: 85%

NHBoc

b10: 97%

O2N

COOBn

NHBoc

b11: 68% (99.9% e.e.)

b9: 75%

F3C

COOMe

O

NHCbz

b12: 98% (99.1% e.e.)

O

MeO

b8: 79%

SF5

F3C

COOMe

N

O

OHC

CN

O

O

O

O

NO2

b13: 99% (99.8% e.e.)

O

O

O X = Cl; b15: 99%

X = Cl; b14: 81%

O O

O

O

O

SO2F

MeO b16: 80%

4

b17: 88%

b20: 90%

OH

b22: 62%

b23: 77%

N H b24b: 77%

N O

COOMe O

N

O NC

Si

N

NH H

O

MeO

F

N

MeO

H H

O

O

O

NH

HN S

b21: 75%

O

CF3

O O

O

S

CHO

CHO b19: 75%

O O S N H

O

S

N

H2N

N

H

H Si tBu

b18: 96%

N H2N

O

Ph

Ph

NC

Ph

N

TBSO

6

N

F

N

O X = Cl; from Indomethacin; b25: 46%

X = Br; from Estrone; b26: 98%

X = Br; from Vandetanib; b27: 73% X = Br; from Flubromazolam; b28: 98%

Br

N

Ge

F Ph a18 99.2% e.e.

F

H2N

S O O 80%

Inversion

H2N

S O O

N

Bpin

O O

Ph

N S

Bpin

b30: 98%

b29: 98.5% e.e. (99.3% e.s.)

HO

Bpin

H2N

B OH b32: 50%

b31: 85%

HO

B OH b33: 65%

Isolated yield. Standard condition: 2 mol% Pd(dba)2, 6 mol% Ligand L10, 1.2 equiv. alkyl carbagermatranes, 1.0 equiv. Ar-X or Alkenyl-X (X = Br, unless otherwise noted), 0.2 M MeCN, 100 or 120 oC, 12 or 16 h. a 95% yield and 85% recovery of GeBr were obtained when the reaction was scaled up to 1.5 mmol. No difference was found compared recovered GeBr with synthesized GeBr. b DMF instead of MeCN.



Page 4 of 8

did not interfere with the cross-coupling reactions. Drug molecules and natural product derivatives underwent alkylation smoothly (b25-b28), reflecting a valuable strategy for late-stage modification of drug molecules. Notably, the chiral secondary benzyl carbagermatrane (a18) gave the corresponding product (b29), of which the configuration was fully inversed under the standard condition, suggesting that the transmetalation was carried out in an “SE2(open) Inv” pathway13a under the additive-free conditions. Finally, we tested the compatibility with boron-containing substrates, since they are the most widely used nucleophiles and their derivatization is of great importance. Bpin (b30), gemdiboryl group (b31) were well tolerated. Remarkably, aryl boronic acids (b32-b33) were also tolerated in spite of the fact that they are easy to transmetalate25.

Next, we examined the scope of substrates of the crosscoupling reactions using various alkyl carbagermatranes and C(sp2) electrophiles (Figure 4). Alkyl carbagermatranes containing cyano (b6), vinyl (b7-b8), acetal (b9), N-phthalimide (b10) were well tolerated. Lserine-derived carbagermatranes reacted with corresponding aryl halides to afford desired products without any racemization (b11-b13). Low reactivity of aryl chlorides is in accord with the fact that electron-deficient phosphine ligands impede the oxidative addition process, and electron-deficient aryl chloride worked better (b14b15). Base-sensitive coumarin (b16) along with TBAFsensitive sulfuryl fluoride (b17) and silyl-protected alcohol (b18) were well preserved. Under standard conditions, satisfying yields were also obtained using olefinic electrophiles instead (b19-b20). Some substrates containing strong polarity functional groups (b21-b24) Figure 5. Tolerance and selectivity of Ge group.

iPr N

iPr BF4 N+

iPr F iPr AlkylFluor N

Ge

OTBS a3

4

B. Fluorination by Ritter's reagent N

Ge

F

78%a

TBAF 1.1 eq RT, 3 h

N

Ge

a20

4

OH

95%

a19

IBX 1.2 equiv. EtOAc-DMSO r.t., 2 h

4

A. TBAF deprotection

N

Ge

O

70%a

a21

4

C. IBX oxidation NC

O B

standard condition O

89%

N

O B

Ge

b34

Pd2(dba)3 / Ruphos NaOtBu Toluene / H2O O

OMe N

Ge

77%a

a9

D. Suzuki coupling

a22

H2O2 / 2M NaOH THF, RT, 2 min quantitative

E. Oxidative hydroxylation N

Ge

OH a23

Isolated yield. a See the supporting information for details.

After the demonstration of the high activity of alkyl carbagermatranes, we next examined their stability (Figure 5). When a3 was handled with TBAF, a most commonly used activator for group 14 nucleophiles, TBS (tert-butyldimethylsilyl) was smoothly removed to furnish alcohol and Ge-C bond remained intact (Figure 5A). Moreover, further handling with Ritter’s deoxyfluorination reagent26 (AlkylFluor) was able to convert OH to F without detecting the broken Ge-C bond (Figure 5B). Meanwhile, a19 was found to be compatible with IBX, and aldehyde-substituted alkyl carbagermatranes were obtained successfully, which further expanded the scope of alkyl carbagermatranes (Figure 5C). Following, alkyl Bpin and alkyl carbagermatranes were compared and it turned out that

their cross-coupling reactions are orthogonal with each other. By applying the standard condition to a9, Ge-C bond was successfully activated and a product with Bpin preserved was obtained with excellent yield. On the other hand, under the condition that B-C bond was activated27, Ge-C bond was also preserved, suggesting that alkyl carbagermatranes are capable of surviving the conditions for Suzuki reactions (Figure 5D). Oxidative hydroxylation is a useful transformation for B-C bond. When oxidative hydroxylation protocol was applied to a9, corresponding product was obtained in quantitative yield and Ge-C bond was intact (Figure 5E). Considering the activity of carbagematranes in cross-coupling reactions, the survival in oxidative condition like IBX and H2O2 is remarkable.

ACS Paragon Plus Environment

Page 5 of 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society

Figure 6. Preparation of bicyclic stapled peptide. Ge

O

H N O

N H

O

H N

a24

HCTU, DIEA, DMF, 1 h

NH2

N H

O

NHFmoc O

N

Ge O

1) HO O

N

2) 20% piperidine/DMF

1)

HO

HO

NHFmoc

NHBoc O


a25


2) 20% piperidine/DMF O

Br

Br

N O

O

H N O

N H

O

H N

N H

O

Br

Ge O

H N

N H

O

Br

O

N

Ge

NHBoc O

N H

HN O

cat. Pd

H N

H2N O O

NH NH

HN

then TFA cocktail overall yield 20%

O

a26 H2N

O O

NH

b35

NH

A. Preparation of bicyclic peptide b35

B. HPLC of crude b35

C. Mass Spectrum of b35

Isolated yield. See the supporting information for experimental details. Cross-coupling reaction condition: 1.0 equiv. a26, 5 mol% Pd(dba)2, 15 mol% Ligand L10, 0.05 M DMF, 120 oC, 16 h.

At last, we found out that a24 and a25 were compatible with standard 9-fluorenylmethyloxycarbonyl solid-phase peptide synthesis (Fmoc-SPPS) procedures, and Ge-containing linear peptide a26 was then synthesized, further intramolecular cross-coupling was able to give bicyclic peptide as product (Figure 6A). After work-up with TFA, the peptide was dissociated from resin, the HPLC analysis suggested clearly main product in the crude b35 (Figure 6B), indicating that our amino acidderived carbagermatranes showed excellent compatibility with Fmoc-SPPS and the cross-coupling reactions on resin (otherwise a mass of byproducts would’ve been detected).The mass spectrum (Figure 6C) confirmed the structure of b35. Although boron-containing reagents have been used for stapled peptides synthesis, it’s limited to biaryl stapled peptides synthesis involving boroncontaining aryl fragment28.

3. CONCLUSION In summary, we have developed the methodology for the synthesis of alkyl carbagermatranes and their crosscoupling reactions. Non-activated secondary alkyl

carbagermatranes show slightly lower activity than its Sn analogue, which need additive for transmetalation as well.24 Meanwhile, primary alkyl carbagermatranes exhibit high activity under base/additive-free conditions and they were also proved stable enough to be compatible with diverse reactions. Our study represents the first example of successful cross-coupling of alkyl germanium reagents, and the above nature of primary/secondary alkyl carbagermatranes in transmetalation under the condition is consistent with Vedejs and Biscoe’s previous observation in Sn chemistry. Synthesis of non-activated chiral secondary alkyl carbagermatranes and study of their stereochemistry during transmetalation are ongoing in our lab.

4. EXPERIMENTAL SECTION General procedure for cross-coupling reactions and recovery of Ge-Br. Pd(dba)2 (1.2 mg, 0.002 mmol), ligand L10 (4.8 mg, 0.006 mmol), aryl halides (0.1 mmol) and the corresponding alkyl carbagermatranes (0.12 mmol) were weighed and transferred to a screw-cap tube with stir bar. The tube was evacuated and backfilled three times with



argon, then CH3CN (0.5 mL) was added and the screw-cap tube was sealed with a Teflon stopper and heated to 120 oC for 16 hours. At the end of the reaction, the reaction mixture was cooled to room temperature and then the tube was settled at -20 oC for 2 hours. Most of Ge-Br was precipitated from the solution which could be recovered through filtration, and filtrate was concentrated to provide the crude product. The crude product was purified by column chromatography or preparative thinlayer chromatogram on silica gel.

ASSOCIATED CONTENT Supporting Information Experimental details and compound characterizations. This material is available free of charge via the Internet at http://pubs.acs.org. Experimental procedures, analysis data, and NMR spectra for products discussed (PDF) Crystallographic data of a18, b29 and GeBr are available free of charge from the Cambridge Crystallographic Data Centre under accession number CCDC-1863713, CCDC1863717 and CCDC-1892813.

AUTHOR INFORMATION Corresponding Author [email protected]

Notes

The authors declare no competing financial interest.

ACKNOWLEDGMENT We thank the National Key R&D Program of China (2017YFA0700104), NSFC (21871239), Youth Innovation Promotion Association of the Chinese Academy of Sciences (2015371) and Fundamental Research Funds for the Central Universities (WK2060190081) for financial support.

REFERENCES (1) (a) Suzuki, A. Cross-Coupling Reactions Of Organoboranes: An Easy Way To Construct C-C Bonds (Nobel Lecture). Angew. Chem. Int. Ed. 2011, 50, 6722-6737. (b) Negishi, E. I. Magical Power of Transition Metals: Past, Present, and Future (Nobel Lecture). Angew. Chem. Int. Ed. 2011, 50, 67386764. (2) For selected reviews about alkyl nucleophiles, see: (a) Jana, R.; Pathak, T. P.; Sigman, M. S. Advances in Transition Metal (Pd, Ni, Fe)-Catalyzed Cross-Coupling Reactions Using Alkyl-Organometallics as Reaction Partners. Chem. Rev. 2011, 111, 1417-1492. (b) Choi, J.; Fu, G. C. Transition metal–catalyzed alkylalkyl bond formation: another dimension in cross-coupling chemistry. Science, 2017, 356, eaaf7230. (3) For selected examples, see: (a) Tellis, J. C.; Kelly, C. B.; Primer, D. N.; Jouffroy, M.; Patel, N. R.; Molander, G. A. SingleElectron Transmetalation via Photoredox/Nickel Dual Catalysis: Unlocking a New Paradigm for sp3–sp2 Cross-Coupling. Acc. Chem. Res. 2016, 49, 1429-1439. (b) Corcé, V.; Chamoreau, L. M.; Derat, E.; Goddard, J. P.; Ollivier, C.; Fensterbank, L. Silicates as

Page 6 of 8

Latent Alkyl Radical Precursors: Visible-Light Photocatalytic Oxidation of Hypervalent Bis-Catecholato Silicon Compounds. Angew. Chem., Int. Ed. 2015, 54, 11414-11418. (c) Jouffroy, M.; Primer, D. N.; Molander, G. A. Base-free photoredox/nickel dual-catalytic cross-coupling of ammonium alkylsilicates. J. Am. Chem. Soc. 2015, 138, 475-478. (4) For selected reviews and example, see: (a) Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Enantioselective and enantiospecific transition-metal-catalyzed cross-coupling reactions of organometallic reagents to construct C–C bonds. Chem. Rev. 2015, 115, 9587-9652. (b) Rygus, J. P.; Crudden, C. M. Enantiospecific and Iterative Suzuki–Miyaura CrossCouplings (Perspective). J. Am. Chem. Soc. 2017, 139, 18124-18137. (c) Wang, C. Y.; Derosa, J.; Biscoe, M. R. Configurationally stable, enantioenriched organometallic nucleophiles in stereospecific Pd-catalyzed cross-coupling reactions: an alternative approach to asymmetric synthesis. Chem. Sci. 2015, 6, 5105-5113. (d) Zhao, S.; Gensch, T.; Murray, B.; Niemeyer, Z. L.; Sigman, M. S.; Biscoe, M. R. Enantiodivergent Pd-catalyzed C–C bond formation enabled through ligand parameterization. Science 2018, 362, 670674. (5) Giannerini, M.; Fananas-Mastral, M.; Feringa, B. L. Direct catalytic cross-coupling of organolithium compounds. Nat. Chem. 2013, 5, 667-672. (6) Knappke, C. E. I.; Jacobi von Wangelin, A. 35 years of palladium-catalyzed cross-coupling with Grignard reagents: how far have we come? Chem. Soc. Rev. 2011, 40, 4948-4962. (7) Knochel, P.; Singer, R. D. Preparation and Reactions of Polyfunctional Organozinc Reagents in Organic-Synthesis. Chem. Rev. 1993, 93, 2117-2188. (8) For related discussion, see: Tellis, J. C.; Primer, D. N.; Molander, G. A. Single-electron transmetalation in organoboron cross-coupling by photoredox/nickel dual catalysis. Science 2014, 345, 433-436. (9) Doucet, H. Suzuki-Miyaura cross-coupling reactions of alkylboronic acid derivatives or alkyltrifluoroborates with aryl, alkenyl or alkyl halides and triflates. Eur. J. Org. Chem. 2008, 2013-2030. (10) Komiyama, T.; Minami, Y.; Hiyama, T. Recent advances in transition-metal-catalyzed synthetic transformations of organosilicon reagents. Acs. Catal. 2017, 7, 631-651. (11) Spivey, A. C.; Gripton, C. J. G.; Hannah, J. P. Recent advances in group 14 cross-coupling: Si and Ge-based alternatives to the Stille reaction. Curr. Org. Synth. 2004, 1, 211226. (12) For discussion about the electronegativity of group 14, see: (a) Allred, A. L.; Rochow, E. G. Electronegativities of carbon, silicon, germanium, tin and lead. J. Inorg. and Nucl. Chem. 1958, 5, 269-288. (b) Rahm, M.; Zeng, T.; Hoffmann, R. Electronegativity Seen as the Ground-State Average Valence Electron Binding Energy. J. Am. Chem. Soc. 2018, 141, 342-351. (13) (a) Hatanaka, Y.; Hiyama, T. Stereochemistry of the crosscoupling reaction of chiral alkylsilanes with aryl triflates: a novel approach to optically active compounds. J. Am. Chem. Soc. 1990, 112, 7793-7794. (b) Matsuhashi, H.; Kuroboshi, M.; Hatanaka, Y.; Hiyama, T. Palladium catalyzed cross-coupling reaction of functionalized alkyltrifluorosilanes with aryl halides. Tetrahedron Letters 1994, 35, 6507-6510. (c) Matsuhashi, H.; Asai, S.; Hirabayashi, K.; Hatanaka, Y.; Mori, A.; Hiyama, T. Palladium-Catalyzed Cross-Coupling Reaction of Alkyltrifluorosilanes with Aryl Halides. Bull. Chem. Soc. Jpn. 1997, 70, 437-444. (14) Nakao, Y.; Takeda, M.; Matsumoto, T.; Hiyama, T. Cross-Coupling Reactions through the Intramolecular


Page 7 of 8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Journal of the American Chemical Society Activation of Alkyl (triorgano) silanes. Angew. Chem., Int. Ed. 2010, 49, 4447-4450. (15) For most of reaction of open-chain alkyl tin reagents, non-activated primary and some special secondary alkyl group were presented, see: (a) Farina, V.; Krishnamurthy, V.; Scott, W. J. The Stille Reaction. Organic reactions 1998, 50, 1-652. (b) Cordovilla, C.; Bartolome, C.; Martinez-Ilarduya, J. M.; Espinet, P. The Stille Reaction, 38 Years Later. Acs. Catal. 2015, 5, 30403053. (16) Vedejs, E.; Haight, A. R.; Moss, W. O. Internal Coordination at Tin Promotes Selective Alkyl Transfer in the Stille Coupling Reaction. J. Am. Chem. Soc. 1992, 114, 6556-6558. (17) (a) Verkade, J. G. Atranes: New Examples with Unexpected Properties. Acc. Chem. Res. 1993, 26, 483-489. (b) Simidzija, P.; Lecours, M. J.; Marta, R. A.; Steinmetz, V.; McMahon, T. B.; Fillion, E.; Hopkins, W. S. Changes in Tricarbastannatrane Transannular N–Sn Bonding upon Complexation Reveal Lewis Base Donicities. Inorg. Chem. 2016, 55, 9579-9585. (18) (a) Li, L.; Wang, C. Y.; Huang, R. C.; Biscoe, M. R. Stereoretentive Pd-catalysed Stille cross-coupling reactions of secondary alkyl azastannatranes and aryl halides. Nat. Chem. 2013, 5, 607-612. (b) Wang, C. Y.; Ralph, G.; Derosa, J.; Biscoe, M. R. Stereospecific Palladium-Catalyzed Acylation of Enantioenriched Alkylcarbastannatranes: A General Alternative to Asymmetric Enolate Reactions. Angew. Chem. Int. Ed. 2017, 56, 856-860. (19) Song, H. J.; Jiang, W. T.; Zhou, Q. L.; Xu, M. Y.; Xiao, B. Structure-Modified Germatranes for Pd-Catalyzed Biaryl Synthesis. Acs. Catal. 2018, 8, 9287-9291. (20) Cross-coupling reactions using Ge-containing reagents have been disregarded for a very long time, one important reason for that is the misunderstanding of the abundance of Ge, besides it’s mostly used for material industry. In fact, the crustal abundance of Ge is only slightly lower than Sn. See: Rudnick, R. L.; Gao, S. Composition of the continental crust in Treatise on geochemistry, Rudnick, R. L.; Holland, H. D.; Turekian, K. K. Eds. (Elsevier, 2003), vol. 3, chap. 3.01, pp. 1-64. (21) The first and only example of the synthesis of carbagermatrane was achieved by Kosugi. However, only one example of alkyl carbagermatrane (nBu-Ge) was presented, and its cross-coupling with PhBr only gave trace yield: Kosugi, M.; Tanji, T.; Tanaka, Y.; Yoshida, A.; Fugami, K.; Kameyama, M.; Migita, T. Palladium-catalyzed reaction of 1-aza-5-germa-5organobicyclo[3.3.3]undecane with aryl bromide. J. Organomet. Chem. 1996, 508, 255-257. (22) (a) Chen, Y.; Peng, H.; Pi, Y. X.; Meng, T.; Lian, Z. Y.; Yan, M. Q.; Liu, Y.; Liu, S. H.; Yu, G. A. Efficient phosphine ligands for the one-pot palladium-catalyzed borylation/Suzuki-Miyaura cross-coupling reaction. Org. Biomol. Chem. 2015, 13, 3236-3242. (b) Lian, Z. Y.; Yuan, J.; Yan, M. Q.; Liu, Y.; Luo, X.; Wu, Q. G.; Liu, S. H.; Chen, J.; Zhu, X. L.; Yu, G. A. 2-Aryl-indenylphosphine ligands: design, synthesis and application in Pd-catalyzed Suzuki–Miyaura coupling reactions. Org. Biomol. Chem. 2016, 14, 10090-10094. (23) Under the optimized condition, we used GeEt4 or GenBu4 instead of alkyl carbagermatranes and no cross coupling product was detected, which shows the impact of atrane.

(24) We conducted cross-coupling reaction between iPrGe and ArBr, and it cannot be realized under additive-free conditions. However, when CuCl was applied in the reaction, a yield of 45% was achieved. With the addition of CuCl and KF (ref. 18a), cross-coupling products were acquired in 74% yield. Br

Ge

+

Pd(dba)2 2 mmol% L10 6 mmol%

i

CH3CN, 100 oC, 16 h

Ph conditions

Yield (GC)

Additive-free CuCl 2eq was added CuCl 2eq + KF 2eq was added

i

Pr

Ph Pr : nPr (GC)

trace 45%

>50 : 1

74%

17 : 1

Stereochemistry of non-activated secondary alkyl carbagermatranes in the reaction has not been studied, which is limited to the fact that currently available chiral secondary alkyl carbagermatranes rely on resolution on chiral stationary phase. We are now working on the synthesis of non-activated chiral secondary alkyl carbagermatranes, and the stereochemistry problem would be studied more conveniently at that time. (25) Byproducts could be polymers and difficult to be detected if p-bromophenyl boronic acid underwent competing Suzuki reaction, thus we conducted intermolecular competing experiment: B(OH)2

1 eq. PhBr 1 eq. hexyl-Ge standard condition

EtOOC 0.1 mmol

Ar = C6H4-p-COOEt

hexyl-Ph 50% yield (GC) Ar-H trace

ArB(OH)2 52% remained (Isolated) Ar-Ar not f ound

Ar-Ph not f ound

Generally, the existence of ArB(OH)2 lower the yield of sp2-sp3 coupling (without optimization). However, only trace of the protonation by-product was detected, and the homocoupling as well as mostly concerning competing Suzuki coupling did not take place. (26) Goldberg, N. W.; Shen, X.; Li, J.; Ritter, T. AlkylFluor: Deoxyfluorination of Alcohols. Org. Lett. 2016, 18, 6102-6104. (27) Yang, C. T.; Zhang, Z. Q.; Tajuddin, H.; Wu, C. C.; Liang, J.; Liu, J. H.; Fu, Y.; Czyzewska, M.; Steel, P. G.; Marder, T. B.; Liu, L. Alkylboronic Esters from Copper-Catalyzed Borylation of Primary and Secondary Alkyl Halides and Pseudohalides. Angew. Chem. Int. Ed. 2012, 51, 528-532. (28) (a) Bois-Choussy, M.; Cristau, P.; Zhu, J. P. Total synthesis of an atropdiastereomer of RP-66453 and determination of its absolute configuration. Angew. Chem. Int. Ed. 2003, 42, 4238-4241. (b) Afonso, A.; Feliu, L.; Planas, M. Solidphase synthesis of biaryl cyclic peptides by borylation and microwave-assisted intramolecular Suzuki-Miyaura reaction. Tetrahedron 2011, 67, 2238-2245. (c) Meyer, F. M.; Collins, J. C.; Borin, B.; Bradow, J.; Liras, S.; Limberakis, C.; Mathiowetz, A. M.; Philippe, L.; Price, D.; Song, K.; James, K. Biaryl-Bridged Macrocyclic Peptides: Conformational Constraint via Carbogenic Fusion of Natural Amino Acid Side Chains. J. Org. Chem. 2012, 77, 3099-3114.



Page 8 of 8

8 7 ACS Paragon Plus Environment

sp3 Cross-Coupling - American Chemical Society

Recommend Documents