Phosphine-Mediated Iterative Arene Homologation Using Allenes

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Phosphine-Mediated Iterative Arene Homologation Using Allenes Kui Zhang, Lingchao Cai, Xing Jiang, Miguel A. Garcia-Garibay, and Ohyun Kwon J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b07403 • Publication Date (Web): 21 Aug 2015 Downloaded from http://pubs.acs.org on August 23, 2015

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Journal of the American Chemical Society

Phosphine-Mediated Iterative Arene Homologation Using Allenes Kui Zhang, Lingchao Cai, Xing Jiang, Miguel A. Garcia-Garibay, and Ohyun Kwon

*

Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095-1569, United States

Supporting Information Placeholder ABSTRACT: A PPh3-mediated multicomponent reaction between o-phthalaldehydes, nucleophiles, and monosubstituted allenes furnishes functionalized non–C2-symmetric naphthalenes in synthetically useful yields. When the o-phthalaldehydes were reacted with 1,3-disubstituted allenes in the presence of PPh2Et, naphthalene derivatives were also obtained, in up to quantitative yields. The mechanism of the latter transformation is straightforward: aldol addition followed by Wittig olefination and dehydration. The mechanism of the former is a tandem γumpolung/aldol/Wittig/dehydration process, established through the preparation of putative reaction intermediates and mass spectrometric analysis. This transformation can be applied iteratively to prepare anthracenes and tetracenes when employing carboxylic acids as pronucleophiles.

The reactivity of electron-deficient allenes under the conditions of phosphine catalysis has been investigated extensively.1 Many reports have appeared of the reactions of monosubstituted allenes with activated olefin2 and imine3 electrophiles to construct carbocyclic and azacyclic compounds. In contrast, few examples are known of the reactions between monosubstituted allenes and aldehyde electrophiles under the influence of phosphine catalysts.4 In general, the union of an allenoate and an aldehyde in the presence of a phosphine results in the formation of an olefin through a Wittig-like process.5 Interestingly, all such reports have described reactions between α- or γ-substituted allenoates and aldehydes. In contrast, Wittig reactions involving simple allenoates are rare. We are aware of only one example of the formation of a pyrrolizine, as a minor product (6%), through intramolecular Wittig olefination between ethyl allenoate (3a) and pyrrole-2-carboxaldehyde.6 Herein, we report Wittig olefination between monosubstituted allenes and o-phthalaldehydes to give highly functionalized naphthalenes and higher-order acenes. Functionalized naphthalenes are valuable building blocks for the synthesis of many important small molecules (e.g., pharmaceuticals, chiral reagents, liquid crystals, organic dyes).7 Many recent syntheses of functionalized naphthalenes have employed costly transition metals or have required several steps to prepare the starting materials.8 Our phosphine-mediated multicomponent cascade reaction described herein—between ophthalaldehydes, nucleophiles, and monosubstituted allenes—is an efficient and mild method for synthesizing functionalized naphthalenes from readily available starting materials. We surveyed the reaction between ethyl allenoate (3a), ophthalaldehyde (1a), and p-toluenesulfonamide by varying the phosphine (stoichiometric), the solvent, the ratio between the reactants, the reaction temperature, and the concentration.9 The

optimized reaction conditions featured PPh3 (1 equiv) as the mediator, an o-phthalaldehyde (1 equiv), a nucleophile (2 equiv), and ethyl allenoate (3 equiv) in CH3CN at 0 °C.

Table 1. Arene homologation using ethyl allenoate 3aa, b CHO •

+ NuH +

R CHO

2

1

CO2Et Nu

R

CH3CN 0 oC

3a

O

4

O OEt

HN

PPh3

CO2Et

S O

X

4h 25% 70%c Cl OEt O

4i 99% (X = H) 4j 95% (X = 4-Br) O

OEt OPh 4m/4m' 92% (X, Y = H, Me)

X

O O

O

O

Y

OEt Ph O

4g 32% 92% c

O

4a 84% (X = 4-Me) 4b 88% (X = H) 4c 78% (X = 4-F) 4d 70% (X = 3-Me) 4e 60% (X = 4-OMe) 4f 85% (X = 2,6-dichloro)

X

O OEt OAc

OEt OPh Y 4n 50% (X = H, Y = NO2) 4n' 46% (X = NO2, Y = H)

OEt X

Cl X

4k 76% (X = OPh) 4l 75% (X = NHTs) X

X

Y

Y &

X

Y

Y

X

4o/4o' 70% (X = CO2Et, Y = CH2OAc)

a

Reaction performed by adding 3a (1.5 mmol) in CH3CN (8 mL) via syringe pump (rate: 2 mL/h) at 0 °C to a solution of an ophthalaldehyde (0.5 mmol), a nucleophile (1 mmol), and PPh3 (0.5 mmol) in CH3CN (4 mL). bIsolated yields. cA sodium carboxylate (1 mmol) was added. Tables 1 and 2 reveal the scope of this three-component cascade reaction. As the nucleophilic component, benzenesulfonamides bearing electron-withdrawing or -donating substituents generated the naphthalene derivatives 4a–f in high yields. With acetic acid and benzoic acid as nucleophiles, the efficiencies of the reactions were poor, giving low yields of the naphthalene derivatives 4g and 4h, respectively. Adding an equimolar amount of sodium acetate or sodium benzoate as a buffer improved the yields of 4g and 4h dramatically.10 When using phenol and p-bromophenol as the nucleophiles, the naphthalene derivatives 4i and 4j, respectively, were formed quantitatively. Examining substituted phthalaldehydes, we found that 4,5-dichlorophthalaldehyde also participated in the reaction, furnishing the naphthalene derivatives 4k and 4l in good yields. Asymmetric 4-methylphthalaldehyde furnished the inseparable isomers 4m and 4m´ in 92% yield. When using 4nitrophthalaldehyde, we separated the two isomers 4n and 4n´ in 50 and 46% yields, respectively.11 Lastly, the combination of benzene-1,2,4,5-tetracarbaldehyde and acetic acid resulted in the expected anthracenes 4o and 4o´ in a combined yield of 70%.12

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Journal of the American Chemical Society Table 2. Arene homologation using phthalaldehyde 1aa, b

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

PPh3

•

CO2Et

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PhO

PhOH

CHO +

+ NuH CHO 2

1a

3

S O

HN

TMS

OBn OAc

4s 87%

S O

PhO

H2O

PPh 3

PhO

CO2Et

CO2Et

OH CO2Et OPh

4r 34% 85%c

X

O

OPh

O OPh

O

CHO PPh3

O

O

O

O HN

CHO

OPh

4p 99% (X = 4-Me) 4q 40% (X = 4-NO2)

O O

S O

C

4i

O OBn

O

CO2Et PPh 3

CO2Et

4

O OEt

HN

R Nu

CH 3CN 0 oC

O

O

4a 84%

PPh3

R

•

PhO

CO2Et PPh3 B

O

4u 98%

4t 73%

a

Reaction performed by adding 3 (1.5 mmol) in CH3CN (8 mL) via syringe pump (rate: 2 mL/h) at 0 °C to a solution of 1a (0.5 mmol), a nucleophile (1 mmol), and PPh3 (1 mmol) in CH3CN (4 mL). bIsolated yields. cNaOAc (1 mmol) was added.

O PPh 3

E

O

D

OH

Although γ-umpolung addition/aldol reaction/Wittig olefination/dehydration is the likely course of events for the phthalaldehyde-to-naphthalene conversion, we could not exclude the alternative sequence of aldol/γ-umpolung/Wittig/dehydration (Scheme 2). In this scenario, the phosphonium dienolate A adds to 1a to form the phosphonium lactolate F. Deprotonation of phenol by lactolate provides the phenoxide nucleophile, γ-umpolung addition of which yields the lactol ylide E, ready for intramolecular Wittig olefination and eventual formation of the naphthalene 4i.

Scheme 2. Aldol/γ-umpolung/Wittig/dehydration sequence We further investigated the reaction scope by treating 1a with a suite of allenes and nucleophiles (Table 2). The reaction of ptoluenesulfonamide and benzyl allenoate provided the naphthalene 4p quantitatively, while that of pnitrobenzenesulfonamide produced 4q in only 40% yield, presumably because of attenuated nucleophilicity. By adding NaOAc as a buffer, the yield of the naphthalene 4r improved from 34 to 85%.10 The combinations of 2-(trimethylsilyl)ethyl buta-2,3dienoate/p-toluenesulfonamide and 2,6-dimethylphenyl buta-2,3dienoate/phenol produced the desired products 4s (87%) and 4t (73%), respectively. The reaction of penta-3,4-dien-2-one and phenol gave the naphthalene 4u in 98% yield. PhO

CO2Et

PPh3

PhOH (R=Ph) α γ

• β

CO2Et

PhO

PPh 3

B

PPh3

PR3

(1) CO2Et

CO2Et PR3

PhO

CO2Et

A

R'CHO

R'

CO2Et O

product

(2)

PR3

While phosphine-catalyzed γ-umpolung additions of nucleophiles to allenoates have been documented amply (eq 1),10,13 reactions between monosubstituted allenes and aldehydes other than salicylaldehyde (derivatives) have been scarce.4a–e In those limited examples, the phosphonium dienolate A has added to the aldehyde at its γ-carbon (eq 2). Based on this prior knowledge, we postulated a credible process involving a sequence of γ-umpolung addition, aldol reaction, Wittig olefination, and dehydration (Scheme 1). Here, the ylide intermediate B from the initial γ-umpolung addition undergoes proton transfer to form the phosphonium enolate C, which adds to 1a to form the lactolate D. Upon proton transfer, the ylide E is formed and undergoes Wittig olefination. Subsequent dehydration provides the naphthalene 4i. Notably, only the γ-umpolung addition product was obtained when 1a was replaced with benzaldehyde, suggesting that the phthalaldehyde plays a crucial role in the progression of the cascade sequence by forming the lactol substructure. Indeed, when we attempted to prepare the adduct between 1a and allenoate, we isolated the corresponding lactol product (see compound 6 in eq 5).

Scheme 1. γ-Umpolung/aldol/Wittig/dehydration sequence

PPh3

CHO

CO2Et •

PPh3

CO2Et

CHO

CO2Et

O

PPh3 F

A

O PhOH

PPh3

PhO

PPh3

PhO

CO2Et 4i

CO2Et

O E

O

OH

G

OH

To establish the greater likelihood between the two possible mechanisms, we prepared the phosphonium salt 5 (precursor to B) and the lactol 6 (precursor to F).9 Mixing 5 with NaH (1 equiv) and 1a (1 equiv) in toluene at room temperature for 4 h yielded the naphthalene 4i in 70% isolated yield (eq 3). Because the optimized conditions for the three-component reaction differed from those of the reaction described above, we also ran the coupling reaction between 1a, 1 equiv of phenol, 1 equiv of the allenoate, 1 equiv of PPh3, and 1 equiv of NaI as an additive (eq 4). This reaction, in toluene at room temperature, went to completion within 6 h and produced the naphthalene 4i in 69% isolated yield. Alternatively, when we mixed the lactol allenoate 6 with PPh3 (1 equiv) and phenol (1 equiv) in toluene at room temperature, we obtained the expected product 4i in 45% yield within only 30 min (eq 5). A control reaction between 1a, phenol (1 equiv), 3a (1 equiv), and PPh3 (1 equiv) in toluene at room temperature resulted in 4i in 70% isolated yield after 6 h (eq 6). Thus, the NaI additive in eq 4 had no effect on the coupling reaction. I

CHO

PPh3

PhO

CO2Et

toluene, rt 4h

CHO

5 CHO +

OEt

•

PhOH +

O

CHO

CO2Et

NaH

+

(3)

OPh 4i 70%yield CO2Et

PPh3, NaI toluene, rt 6h

(4) OPh 4i 69% yield

OH O 6

•

+

PPh3

PhOH

toluene, rt 0.5 h

CO2Et

CHO +

PhOH +

CHO

CO2Et

OEt

• O

(5)

OPh 4i 45% yield PPh3 toluene, rt 6h

CO2Et OPh

(6)

4i 70% yield

2 ACS Paragon Plus Environment

Consequently, we envisioned a reaction between an allenoate and 1a in the absence of a pronucleophile. The presumed intermediate F´, we deduced, might form the ylide H, which should undergo facile intramolecular Wittig olefination and dehydration to form the naphthalene 7a (eq 7). Delightedly, the reaction between 1a, ethyl 2,3-pentadienoate (1 equiv), and PPh3 (1 equiv) in toluene at room temperature for 50 min gave 7a in 75% isolated yield (eq 8). This outcome not only provides an alternative pathway for arene homologation but also discounts the aldol–before–γ-umpolung addition scenario. Considering that the γ-umpolung/Wittig/dehydration sequence of the lactol 6 took 30 min and the aldol/Wittig/dehydration sequence of 1a and ethyl 2,3-pentadienoate (through intermediate F´) took 50 min, the three-component arene homologation would have been complete within 1 h if the reaction had occurred through the aldol-first route. Therefore, the reaction likely proceeds through initial γ-umpolung addition, with the rate-limiting step being not the aldol addition of C to 1a but the conversion of the ylide B to the enolate C. PPh3

CO2Et CO2Et

O F'

O

O

H

CO2Et PPh 3

O PPh 3

263

279

(7)

OH Ph3P O

H2 O

PhO

CO2Et

CO2Et

O

PPh3

PPh3

B 491

A 375

F 509

O

1: TOF MS ES+ 2.61e5

293.1097

100

3 min 263.0997

375.1516

294.1141 376.1567 295.0722

491.1766 492.1800 523.2016

377.1583

342.1001

587.1132

0 1: TOF MS ES+ 4.21e5

375.1490

100

40 min 279.0921 293.1078

263.0977

491.1738

376.1532 294.1119 342.1010 301.0724

492.1775 523.2002

343.1072 377.1583

493.1807

579.1619 580.1657

0 1: TOF MS ES+ 3.60e5

375.1516

100

4h 279.0952 293.1105

491.1775 376.1561 263.1016

294.1151

509.1890 377.1616 407.1710

295.1130 342.1019

0 250

PPh3

CO2Et

PPh3

%

Although inconclusive, the experiments in eqs 3–6 hinted at the following possibility. If the aldol reaction occurred before the umpolung reaction, the rate-limiting step for the scenario in Scheme 2 would be the addition of the phosphonium dienolate A to 1a because the conversion of the lactol 6 to the product took only 30 min. If the umpolung addition were the first event of the cascade reaction (i.e., Scheme 1), the conversion of the ylide B to the phosphonium enolate C or the addition of the enolate C to 1a would likely be the slowest step. Indeed, the pKa of the ylide B (21 in DMSO) is lower than that of the enolate C (30 in DMSO).14 Thus, despite unfavorable thermodynamics, the phosphonium dienolate A is likely to be funneled into the ylide B as a result of rapid protonation by acidic phenol and the subsequent γ-addition.

%

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


%

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445.1012

557.1824 523.2052 525.2037 558.1854

m/z 275

300

325

350

375

400

425

450

475

500

525

550

575

600

Figure 1. High-resolution mass spectra recorded during the reaction of eq 6 (m/z values for [M + H]+ or [M + Na]+ ions) Table 3. Two-component arene homologationa, b

7a

O CHO + CHO

•

CO2Et

PPh3 rt, toluene 50 min

CO2Et (8)

CHO +

R1

7a 75%

R2

R3

• O

CHO

PPh2Et

7

1

Monitoring the reaction with high-resolution mass spectrometry (HRMS) confirmed our suspicions. After a reaction time of 3 min (8.3% 4i formation), the HRMS trace displayed A ([M + H]+, m/z 375.1514) and B ([M + Na]+, m/z 491.1752), but no F ([M + H]+, m/z 509.1882).9 Although the reaction progressed steadily with the peak for B clearly present throughout, the peak corresponding to the phosphonium lactolate F was barely evident after 40 min (37.5% 4i formation) and was clearly visible only after 4 h (63.2% 4i formation), suggesting that γ-addition–first is the dominant reaction pathway. Examination of a range of phosphines, solvents, and reaction temperatures revealed that addition of γ-substituted allenoates (2 equiv) to a mixture of a phthalaldehyde and PPh2Et (1 equiv) in toluene at room temperature was optimal for arene homologation (Table 3). After stirring for 30 to 45 min, we obtained the desired arenes 7a–g in excellent yields. 4,5-Dichlorophthalaldehyde was converted quantitatively to the naphthalene 7b. When using naphthalene-2,3-dicarbaldehyde in this reaction, the anthracene 7c was obtained in 100% isolated yield. Ethyl hexa-2,3-dienoate and ethyl 4-cyclopentylbuta-2,3-dienoate were produced the naphthalenes 7d and 7e, respectively, as E-stereoisomers. tertButyl penta-2,3-dienoate and benzyl penta-2,3-dienoate gave their expected products 7f (93%) and 7g (97%), respectively.

O

R3

R1

rt, toluene 30~45 min

R2

O OEt

Cl

O OEt

OEt

Cl 7a 97%

7b 100% O

7c 100% O

O OEt

7d 95%

OEt

7e 96%

OX

7f 93% (X = t-Bu) 7g 97% (X = Bn)

a Reaction performed with a dialdehyde (0.4 mmol), an allenoate (0.8 mmol), and PPh2Et (0.4 mmol) in toluene (4 mL) at room temperature. bIsolated yields.

The utility of the multicomponent reaction is further illustrated in the synthesis of the 2,3-disubstituted tetracene 11 (Scheme 3). Reduction of the ester groups of the naphthalene 4g yielded a diol, which was oxidized to naphthalene-2,3dicarbaldehyde (8) with high efficiency. Repetition of the annulation, reduction, and oxidation sequence provided anthracene-2,3-dicarbaldehyde (10), which underwent another annulation to provide the tetracene 11. A variety of 2,3-substituted tetracenes should be readily obtainable from 11 through functional group manipulation, with potential applications in solar cells and light-emitting materials.15


Journal of the American Chemical Society Scheme 3. Iterative synthesis of anthracene and tetracene

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

• CO2Et NaOAc, HOAc

CHO CHO •

CO2Et

PPh3 92%

4g

CO2Et

CO2Et

NaOAc, HOAc

OAc

PPh3 85%

9

•

CO2Et NaOAc, HOAc PPh3 72%

CHO

1. LAH

OAc 2.Swern ox. 84%

1. LAH 2.Swern ox. 68%

CHO 8 CHO CHO 10

CO2Et OAc 11

Figure 2. Excitation (solid lines) and emission (dashed lines) spectra of 4g (blue lines), 9 (green lines), and 11 (red lines). We obtained fluorescence excitation and emission spectra for compounds 4g, 9, and 11 (Figure 2). Stronger transitions appeared in the range 250–300 nm, with weaker transitions in the range 300–500 nm. A bathochromic shift occurred upon proceeding from 4g (326 nm) to 9 (358 nm) to 11 (450 nm). A bathochromic shift also occurred in the fluorescence emissions from 4g to 9 to 11, with 0–0 transitions at 342, 406, and 495 nm, respectively. The quantum yields for the substituted polyacenes 4g, 9, and 11 were 0.18, 0.65, and 0.15, respectively. These observations match well with reported photophysical data of 2-carbonylpolyacenes.16 In conclusion, we have developed a phosphine-mediated multicomponent reaction between allenes, o-phthalaldehydes, and nucleophiles that provides non–C2-symmetric naphthalene, anthracene, and tetracene derivatives. A mechanistic investigation involving the synthesis of putative intermediates and reaction monitoring through HRMS revealed that this conversion occurs through a γ-umpolung/aldol/Wittig/dehydration cascade. A combination of phthalaldehydes and 1,3-disubstituted allenes also produces naphthalenes through an aldol/Wittig/dehydration sequence. This arene homologation can also be applied iteratively to prepare higher-order acenes.

ASSOCIATED CONTENT Supporting Information. Experimental procedures and analytical data (PDF). This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author [email protected]

ACKNOWLEDGMENT The NIH (GM071779) is acknowledged for financial support.

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(i) Han, X.; Wang, S.-X.; Zhong, F.; Lu, Y. Synthesis 2011, 1859. (j) Zhao, Q.; Han, X.; Wei, Y.; Shi, M.; Lu, Y. Chem. Commun. 2012, 48, 970. (3) Selected examples: (a) Xu, Z.; Lu, X. Tetrahedron Lett. 1997, 38, 3461. (b) Xu, Z.; Lu, X. J. Org. Chem. 1998, 63, 5031. (c) Mercier, E.; Fonovic, B.; Henry, C. E.; Kwon, O.; Dudding, T. Tetrahedron Lett. 2007, 48, 3617. (d) Fang, Y. Q.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 5660. (e) Gaun, X. Y.; Wei, Y.; Shi, M. J. Org. Chem. 2009, 74, 6343. (f) Meng, X. T.; Huang, Y.; Chen, R. Y. Org. Lett. 2009, 11, 137. (g) Sun, Y. W.; Guan, X. Y.; Shi, M. Org. Lett. 2010, 12, 5664. (h) Chen, X. Y.; Lin, R. C.; Ye, S. Chem. Commun. 2012, 48, 1317. (i) Han, X.; Zhong, F.; Wang, Y.; Lu, Y. Angew. Chem. Int. Ed. 2012, 51, 767. (j) Henry, C. E.; Xu, Q.; Fan, Y. C.; Martin, T. J.; Belding, L.; Dudding, T.; Kwon, O. J. Am. Chem. Soc. 2014, 136, 11890. (4) (a) Zhu, X. F.; Henry, C. E.; Wang, J.; Dudding, T.; Kwon, O. Org. Lett. 2005, 7, 1387. (b) Dudding, T.; Kwon, O.; Mercier, E. Org. Lett. 2006, 8, 3643. (c) Zhu, X.-F.; Schaffner, A.-P.; Li, R. C.; Kwon, O. Org. Lett. 2005, 7, 2977. (d) Creech, G. S.; Kwon, O. Org. Lett. 2008, 10, 429. (e) Creech, G. S.; Zhu, X. F.; Fonovic, B.; Dudding, T.; Kwon, O. Tetrahedron 2008, 64, 6935. (f) Sun, Y. W.; Guan, X. Y.; Shi, M. Org. Lett. 2010, 12, 5664. (5) (a) He, Z. R.; Tang, V.; He, Z. J. Phosphorous Sulfur Silicon Relat. Elem. 2008, 183, 1518. (b) Xu, S. L.; Zhou, L. L.; Zeng, S.; Ma, R. Q.; Wang, Z. H.; He, Z. J. Org. Lett. 2009, 11, 3498. (c) Xu, S. L.; Zou, W.; Wu, G. P.; Song, H. B.; He, Z. J. Org. Lett. 2010, 12, 3556. (d) Khong, S. N.; Tran, Y. S.; Kwon, O. Tetrahedron 2010, 66, 4760. (e) Xu, S. L.; Chen, R. S.; He, Z. J. J. Org. Chem. 2011, 76, 7528. (f) Jacobsen, M. J.; Funder, E. D.; Cramer, J. R.; Gothelf, K. V. Org. Lett. 2011, 13, 3418. (g) Qin, Z.; Ma, R.; Xu, S.; He, Z. J. Tetrahedron 2013, 69, 10424. For exceptions, see: ref. (d); ref. (g); (h) Ma, R. Q.; Xu, S. L.; Tang, X. F.; Wu, G. P.; He, Z. J. Tetrahedron 2011, 67, 1053. (6) Virieux, D.; Guillouzic, A. F.; Cristau, H. J. Tetrahedron 2006, 62, 3710. (7) (a) Harvey, R. G. Polycyclic Aromatic Hydrocarbons; Wiley-VCH: New York, 1996. (b) Waston, M. D.; Fethtenkötter, A.; Müllen, K. Chem. Rev. 2001, 101, 1267. (c) De Koning, C. B.; Rousseau, A. L.; van Otterlo, W. A. L. Tetrahedron 2003, 59, 7. (8) Selected examples: (a) Feng, C.; Loh, T. P. J. Am. Chem. Soc. 2010, 132, 17710. (b) Fukutani, T.; Hirato, K.; Satoh, T.; Miura, M. J. Org. Chem. 2011, 76, 2867. (c) Kocsis, L. S.; Benedetti, E.; Brummond, K. M. Org. Lett. 2012, 14, 4430. (d) Kang, D. L.; Kim, J.; Oh, S.; Lee, P. H. Org. Lett. 2012, 14, 5636. (e) Geary, L. M.; Chen, T. Y.; Montgomery, T. P.; Krische, M. J. J. Am. Chem. Soc. 2014, 136, 5920. (f) Pham, M. V.; Cramer, N. Angew. Chem. Int. Ed. 2014, 53, 3484. (9) See the Supporting Information for more details. (10) Trost, B. M.; Li, C. J. J. Am. Chem. Soc. 1994, 116, 3167. (11) The structure of 4n´ was established using X-ray crystallography.9 (12) The structures of 4o and 4o´ were identified using 1H NMR spectroscopy. See the detailed information in the Supporting Information. (13) Selected examples: (a) Cristau, H.-J.; Viala, J.; Christol, H. Tetrahedron Lett. 1982, 23, 1569. (b) Lu, X.; Zhang, C. Synlett 1995, 645. (c) Chen, Z.; Zhu, G.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X. J. Org. Chem. 1998, 63, 5631. (d) Smith, S. W.; Fu, G. C. J. Am. Chem. Soc. 2009, 131, 14231. (e) Chung, Y. K.; Fu, G. C. Angew. Chem. Int. Ed. 2009, 48, 2225. (f) Lundgren, R. J.; Wilsily, A.; Marion, N.; Ma, C.; Chung, Y. K.; Fu, G. C. Angew. Chem. Int. Ed. 2013, 52, 2525. (14) Evans D. A. Evans pKa Table. http://evans.harvard.edu/pdf/evans_pKa_table.pdf. (15) (a) Bendikov, M.; Wudl, F.; Perepichka, D. F. Chem. Rev. 2004, 104, 4891. (b) Anthony, J. E. Chem. Rev. 2006, 106, 5028. (c) Burdett, J. J.; Bardeen, C. J. Acc. Chem. Res. 2013, 46, 1312. (16) Nehira, T.; Parish, C. A.; Jockusch, S.; Turro, N. J.; Nakanishi, K.; Berova, N. J. Am. Chem. Soc. 1999, 121, 8681.


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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


TOC Graphic EWG NuH +

•

Nu

EWG

EWG PPh3

R2 CHO

PR3 R2 R1

•

EWG

R1

Nu 23 examples up to 99% yield

CHO EWG

EWG PPh2Et

R2 7 examples R1 up to 100% yield



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

67x29mm (300 x 300 DPI)


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19x2mm (300 x 300 DPI)



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

99x65mm (300 x 300 DPI)


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118x23mm (300 x 300 DPI)



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

142x72mm (300 x 300 DPI)


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53x20mm (300 x 300 DPI)



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

67x35mm (300 x 300 DPI)


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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


69x38mm (300 x 300 DPI)



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

85x53mm (300 x 300 DPI)


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53x21mm (300 x 300 DPI)



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PPh 3 CO 2Et PPh 3

O PPh 3

CO 2Et

O

PPh 3

PPh 3 A 375

279

263

PhO

CO 2Et

B 491

F 509


293.1097

100

O

%

263.0997

375.1516

294.1141 376.1567 295.0722

0

342.1001

491.1766 492.1800 523.2016

377.1583


375.1490

100

587.1132

279.0921

%

293.1078

263.0977

491.1738

376.1532 294.1119 342.1010 301.0724

492.1775 523.2002

343.1072 377.1583

493.1807

579.1619 580.1657

0 1: TOF MS ES+ 3.60e5

375.1516

100

279.0952 293.1105

%

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

491.1775 376.1561 263.1016

294.1151

509.1890

295.1130 342.1019

0 250

275

300

325

350

377.1616 407.1710

375

400

425

445.1012

450

475

500

557.1824 523.2052 525.2037 558.1854

525

550

575

600

m/z


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26x5mm (300 x 300 DPI)



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

130x60mm (300 x 300 DPI)


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70x34mm (300 x 300 DPI)



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Phosphine-Mediated Iterative Arene Homologation Using Allenes

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