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General, Auxiliary-Enabled Photoinduced PdCatalyzed Remote Desaturation of Aliphatic Alcohols Marvin Parasram, Padon Chuentragool, Yang Wang, Yi Shi, and Vladimir Gevorgyan J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 09 Oct 2017 Downloaded from http://pubs.acs.org on October 9, 2017
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Journal of the American Chemical Society
General, Auxiliary-Enabled Photoinduced Remote Desaturation of Aliphatic Alcohols
Pd-Catalyzed
Marvin Parasram, Padon Chuentragool, Yang Wang, Yi Shi, and Vladimir Gevorgyan* Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, United States Supporting Information Placeholder ABSTRACT: A general, efficient, and site-selective visible
light-induced Pd-catalyzed remote desaturation of aliphatic alcohols into valuable allylic-, homoallylic-, and bishomoallylic alcohols has been developed. This transformation operates via a hybrid Pd-radical mechanism, which synergistically combines the favorable features of radical approaches, such as a facile remote C–H HAT step, with that of transition metal-catalyzed chemistry (selective β-hydrogen elimination step). This allows achieving superior degrees of regioselectivity and yields in desaturation of alcohols compared to those obtained by the state-of-the-art desaturation methods. The HAT at unactivated C(sp3)–H sites is enabled by the easily installable/removable Si-auxiliaries. Formation of the key hybrid alkyl Pd-radical intermediates is efficiently induced by visible light from alkyl iodides and Pd(0) complexes. Notably, this method requires no exogenous photosensitizers or external oxidants.
Scheme 1. Desaturations Methods in Aliphatic Systems a) TM-catalyzed approach: Yu,4a Boudoin,4b Catellani4c B TM
H DG
n 1 o, 2 o
H
DG
TM-cat. 120-150 oC
DG
n CMD mechanism
b) Radical/cationic approach for γ-/δ- desaturation, Baran5b Hβ O2S
Hδ
O Hγ
Et2N3
H+
R
O2S
Hβ
Hδ 3o
O
Hγ
[O]
R
O2S
Me
Hδ
O -Hβ or Hδ
R
Hγ
selective HAT at unactivated γ-tertiary C–H site
O R homoallylic alcohols
[O] Hβ
Me
Ts
difficult to control H+-elimination
Me cationic intermediates
c) Our prior work: desaturation involving hybrid Pd-radical 1,5-HAT at proximal activated C(sp3)–H site7 Hβ Et2Si
Pd-cat.
O
I
Hα
R
PhEt2Si
Et2Si
Hβ
O 3o Hα
O
R silyl enol ethers
visible light rt Hβ
Alkenes are one of the most widely used functional groups in organic synthesis, broadly found in a wide range of bioactive molecules and natural products.1 Methods toward synthesis of these privileged motifs often involve non-universal strategies that require pre-functionalization of starting materials at the desired reaction site. Unfortunately, methods for synthesis of alkenes via direct desaturation of aliphatic chains are less explored. This is mainly attributed to the inherent difficulty of activating the kinetically inert C(sp3)–H bonds. Although, considerable progress has been made in converting unactivated C–H bonds into valuable C–C and C– heteroatom fragments via transition metal (TM) catalysis,2 a synthetically appealing selective site-controlled desaturation of aliphatic systems into privileged olefins still remains underdeveloped. Modern TM-catalyzed approaches typically operate via a direct transfer-hydrogenation process3 or a directed concerted metalation-deprotonation (CMD) pathway.4 Between the two pathways, the latter approach is an attractive option owning to its site-controlled capability (Scheme 1a). Nevertheless, this method suffers from low selectivity and efficiency, limited substrate scope, and harsh reaction conditions. Moreover, the site of functionalization is often restricted based on formation of a favorable TM-cyclic intermediate
n limited scope
Et2Si
R
O
-Hβ
R I-Pd(I)
Hα
I-Pd(I) selective HAT at activated α-tertiary C–H site
hybrid Pd-radical intermediates
d) This work: desaturation involving hybrid Pd-radical 1,n-HAT at remote unactivated C(sp3)–H sites Hβ
I Si R2
Hδ
Hα
Hγ
H
Pd-cat.
O
HO
visible light rt
Hε
n
R = i-Pr, Me Hβ
I-Pd(I)
mild conditions no exogenous oxidants and photosensitizers
Hδ
H
H
3 o, 2 o
O Si R2
Hα
Hγ
-H
O
Hε
A selective HAT at unactivated β-,γ-,δ- C–H sites
n=0-2
allylic-, homoallylic-, and bis-homoallylic alcohols generally good yields and high regioselectivity
Si R2
n
H I-Pd(I)
hybrid Pd-radical intermediates
controlled β-H elimination
B
and is limited to activation of 1° and 2° γ-/δ -C–H bonds (Scheme 1a). To the best of our knowledge, there have been no reports on TM-catalyzed functionalization of unactivated 3° C–H bonds. Emerging radical strategies, however, have provided solutions for 3° C–H bond functionalization.5,6 Thus, in Baran’s pioneering work,5b he showcased a guided C– H desaturation of aliphatic systems involving a tetherpossessing an aryl radical hydrogen abstracting group, which due to geometrical constraints, favors γ-C–H HAT at 3° site
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(Scheme 1b). Owing to the nature of this transformation, the translocated radical undergoes oxidation with an external oxidant, followed by elimination into the alkene moiety. While groundbreaking, in some cases, this approach suffers from regioselectivity issues due to a non-selective proton loss step from the formed cationic intermediate. Overall, both TM-catalyzed and radical approaches are complementary but still have certain limitations. We have recently reported visible light-induced formation of hybrid aryl Pd-radical intermediate capable of HAT process, and a subsequent β-hydrogen elimination step to furnish an alkene moiety. Due to the favorable 1,5-HAT process of the aryl hydrogen atom-abstracting group of the silicon tether, the H atom abstraction occurred exclusively at the proximal α-C–H site, thus resulting in the α-/βdesaturation of silyl ethers into silyl enols (Scheme 1c).7 Herein, we report a general, efficient, selective, and mild visible light-induced8 Pd-catalyzed remote desaturation of aliphatic alcohols. This method involves unprecedented, for alkyl hybrid Pd-radical species,9 HAT process at unactivated C(sp3)–H sites10 (Scheme 1d). The abstraction at β-, γ-, or δsites is enabled by employment of easily installable/removable Si-auxiliaries11 (A). The formed transposed hybrid species B furnishes a remote alkene moiety upon a controlled β-hydrogen elimination step, thus resulting in desaturated alcohols with degrees of regioselectivity, unseen, for radical methods. Based on our recent work on the formation of silyl methyl hybrid-Pd radicals from iodomethylsilanes,12 we hypothesized that if this moiety (T1, Scheme 2) could be engaged in a 1,6HAT event,13,14 it would subsequently enable γ-/δdesaturation toward important homoallylic alcohols.15 Furthermore, based on the usually selective β-hydride elimination step in the hybrid Pd-radical mechanism,9b,12 it was anticipated that the alkenol product would be formed with high degrees of regiocontrol. Accordingly, we were eager to validate this premise on desaturation of challenging alcohol derivative 1a, which under conditions of reported radical/cationic protocol5b resulted in nearly equal mixture of regioisomeric alkenols (2a-1, 2a-1’, Scheme 2a). We were pleased to find that exposure of T1-tethered alcohol 1a-T1 to our optimized16 photocatalytic conditions resulted in γ-/δdesaturation product 2a in 77% yield as a single regioisomer, thus fully supporting the above hypothesis! Notably, this outcome represents the first remote Pd-catalyzed 3° C–H functionalization event under mild and neutral conditions. Finally, it deserves mentioning that this photochemical transformation does not require the employment of exogenous photosensitizers17 or external oxidants. Next, the generality of the γ-/δ-desaturation of aliphatic alcohols toward homoallylic alcohols was investigated (Table 1). After completion of the desaturation reaction, except for
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Scheme 2. Comparison Study a) Radical/cationic approach: Baran's results5b O
O
N3Et2
T0 = Me
H
O
TFA (3 equiv), 60 oC - orTfOH (2 equiv), rt
S
2a-1
O
TEMPO (1 equiv), CH3NO2
Ts
2a-1’ 55%, 2a-1 : 2a-1’ = 1.15 : 1
O T
b) Hybrid Pd-radical approach: This work
1a
i-Pr Si
T1 =
Ts
+
OH
10 mol % Pd(OAc)2 20 mol % L 2 equiv Cs2CO3
i-Pr I
2a +
PhH, Blue LED, rt, 24 h then, TBAF, 2 h
OH
2a’ 77%, 2a : 2a’ = 100 : 0
Table 1. γ -/δ - Desaturation of Alcoholsa T1/2
O
10 mol % Pd(OAc)2 20 mol % L 2 equiv Cs2CO3
H R2
R1
δ
γ H
1
T1/2
O
R1
0.1 M, PhH, Blue LED, rt , 12-48 h then, 4-10 equiv TBAF
H
R2
γ
Me Me I Si
T1
L
OH
HO HO
OH
OH 2b, 48%b
2d, 71%,b 4.7 : 1 r.r.
2c, 47%b
H
2e,
P(t-Bu)2
T2
2a, 77%b
N H
i-Pr i-Pr I Si
Fe
δ
2
OH
Boc
PPh2
OH
OH
i-Pr i-Pr Si Me O
i-Pr i-Pr Si Me O
OH
67%b,d
2f,
79%c
2g,
70%c,d
2h, 77%b,e
2i, 76%b,e 9.5 : 1 r.r. i-Pr
OH
H OH
HO
2j, 80%c
2k, 73%c
2l, 68%c 3.3 : 1 r.r.
O
OH
2m, 53%b
HO 2n, 43%b 10 : 1 r.r.
H
HO
2o, 65%b
a
Isolated yields, r.r. = regioisomeric ratio. bT1 was used. cT2 was used. dContains minor amount of hydrodehalogenation byproduct. eThe desilylation step (TBAF) was omitted.
the cases with volatile low-molecular weight alkenols, the silyl-based tethers were in one-pot routinely removed by treatment with TBAF. It was found that various primary alcohols, possessing functional groups such as alcohols (1b, c) and amides (1e), underwent smooth γ-/δ-desaturation to generate their respective homoallylic derivatives (2b, c, e) in good yields. Then, desaturation of bulkier secondary alcohols was tested (1f–1j). For these cases, due to the relative ease of installation, we opted to employ sterically less hindered dimethyl(iodomethyl)silane tether T2 instead of bulkier T1. Desaturation of naturally occurring (-)-menthol (1f), possessing two equally distant sites of functionalization, selectively furnished chiral building block (-)-isopulegol (2f) in 79% yield due to a favorable transition state for an HAT event at the isopropyl group.18,19 Endogenous alkene moiety 1g did not compromise the reaction, as diene 2g was formed efficiently.
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Desaturation of 1h proceeded uneventfully, producing alkene 2h in good yield. Notably, substrates 1i and 1j, which along with Hγ, possess competitive Hβ and Hδ sites of abstraction, reacted selectively at the γ-C–H sites, thus producing 2i and 2j in good yields and high regioselectivity. Based on these, as well as on the results of a direct competition between Hβ and Hδ sites (vide infra, 2z using T1) and the kinetic studies,16 the following reactivity preference order for silyl tethers T1 and T2 for HAT in substrates possessing 3° C–H sites with similar BDEs20 was revealed: 1,6 HAT of Hγ >1,5 HAT of Hβ > 1,7 HAT of H. Tertiary alcohols were also compatible with our desaturation protocol (2k, l). Importantly, HAT at challenging 2° C–H bonds of tertiary alcohol 1l was also achieved, producing 2l in good yield. Furthermore, this method proved competent for desaturation of complex natural products and derivatives. Thus, remote desaturation of abietol (1m) generated its dehydrogenated analog 2m in moderate yield. Moreover, γ/δ-desaturation of secondary cis-androsterone (1n) and tertiary cholestanol derivative (1o) worked well, furnishing 2n and 2o in reasonable yields. After developing efficient method for γ-/δ-desaturation of aliphatic alcohols into homoallylic alcohols, we aimed at extending this protocol toward formation of valuable allylic alcohols21 via β-/γ-desaturation process involving 1,5 HAT (Table 2). Delightfully, it was found that secondary and tertiary alcohols bearing an isopropyl unit underwent selective desaturation to generate the corresponding alcohols in a highly efficient manner (2p–2u). Subjecting 5-membered cycloalkane 1v to the reaction conditions unexpectedly resulted in the formation of the thermodynamically more stable endo-isomer 2v. In contrast, 6-membered β-methyl cycloalkanes produced the kinetic exo-methylene products 2w–x in reasonable yields. Complex limonene derivative 1y underwent β-/γ-desaturation producing exo-alkene 2y in 70% yield. Expectedly, based on the Si-tether reactivity preference for HAT (vide supra), desaturation of ambident substrate 1z, possessing competing β-/γ- and δ-/ε- desaturation sites, preferably occurred at the former site, producing allylic alcohol 2z in good yield. Finally, we examined the boundaries of this methodology toward δ-/ε- desaturation of alcohols. Gratifyingly, primary (1aa), secondary (1ab),and tertiary alcohols (1ac) all produced the δ-C–H functionalized products in moderate to excellent yields! Likewise, desaturation of complex derivative dehydroabietol 1ad resulted in δ-/ε- desaturation product 2ad in moderate yield.
Table 2. β -/γ - and δ -/ε - Desaturation of Alcoholsa T1/2 T1/2
O
H
β
R1
H
δ
γ
ε
H 1
O
β
R1
T1/2
O
Me Me I Si
δ
R1
Me i-Pr Si i-Pr O
T1
or
O
ε
T2
R2
2 OH
i-Pr i-Pr I Si
γ
R2
0.1 M, PhH, Blue LED, rt , 12-48 h then, 4-10 equiv TBAF
H R2
TMS
OH
Fe 2p, 80%b 3.1 : 1 r.r.
2s, 48%c
2q, 71% (NMR)b,d 2r, 87% (NMR)c,d
OH
OH
O
t-Bu Me 2t, 82%c i-Pr O Si i-Pr Me
O
i-Pr Si i-Pr Me
2we, 50%b,d i-Pr
OH
2xe, 42%b,d
i-Pr Si i-Pr Me
2ve, 49%b,d
2u, 66%c
OH
O
2z, 73%b 8 : 1 r.r.
2ye, 70%c
i-Pr Si
Me
2aa, 57%b,d,f i-Pr
OH
OH
2ab, 77%c 7.3 : 1 r.r.
2ac, 89%c
b OH 2ad, 40%
a
Isolated yields, r.r. = regioisomeric ratio. bT1 was used. cT2 was used. dThe desilylation step (TBAF) was omitted. eFor 1v-1y, the trans precursor was used. fContains minor amount of hydrodehalogenation by-product.
the Pd(0) catalyst by alkyl iodide 1f.16 Based on the aforementioned studies, the following mechanism is proposed (Scheme 3). Visible light induction of the in-situ generated Pd(0) complex produces the active photoexcited Pd(0) complex, which engages in an SET process with alkyl iodide 1 to form alkyl hybrid intermediate 3. Next, the formed radical species undergoes a rate-limiting 1,n-HAT event (for n=5, kH/kD=3.516) to generate translocated alkyl hybrid Pd-radical species 4. The latter, either via a recombination of 4 with the putative Pd(I) intermediate followed by a β-hydride elimination from 5 (path A) or via a direct abstraction of β-hydrogen atom22 by Pd(I) species (4→2, path B),23 produces the alkene 224 and regenerates the Pd catalyst. Scheme 3. Proposed Mechanism B HbI
LnPd(0)*
B
Hb
I
O
T Ha T
hν 450 nm
HbPd(II)I
O
LnPd(0)
n
SET via 1
n
Ha
1
-
2
T
O
n
A
n 3
Pd(II)I
β-H-elimination
Hb
Pd(I)I O T
Hb
Ha
5
The results of performed radical trap-, radical clock-, and isotope labeling studies,16 supported the radical nature of this transformation. The UV-Vis analysis revealed that the Pd(0) complex is the photoabsorbing species. Moreover, the SternVolmer studies supported quenching of the excited state of
10 mol % Pd(OAc)2 20 mol % L 2 equiv Cs2CO3
Ha
direct H-abstraction B Hb
Ha T
O
n 4
1,n-HAT
Pd(I)I
3
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In summary, we have developed a room temperature, auxiliary-enabled visible light-induced Pd-catalyzed remote β-/γ, γ-/δ-, and δ-/ε- desaturation of alcohols. The hybrid Pdradical nature of this protocol enabled efficient functionalization of unactivated C–H sites. Moreover, the desaturation products were formed with superior degrees of regioselectivity compared to the state-of-the-art radical/cationic methods due to a better-controlled Pd-involved β-hydrogen elimination step. Overall, this transformation represents the first practical catalytic desaturation of aliphatic alcohols. We believe that this approach addresses the shortcomings of prior art and provides a new avenue for targeted aliphatic C–H functionalization under photoinduced transition metalcatalysis. ASSOCIATED CONTENT Experimental procedures and compound characterization data. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author
[email protected] Notes
The authors declare no competing financial interest.
A CKNOWLEDGMENT This research was supported by the National Science Foundation (CHE-1663779) and the National Institutes of Health (GM120281). REFERENCES
(1) Comprehensive Organic Transformations; Larock, R. C.; 2nd Ed.; Wiley: New York, 1999. (2) (a) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Chem. Rev. 2017, 117, 8754. (b) Daugulis, O.; Roane, J.; Tran, L. D. Acc. Chem. Res. 2015, 48, 1053. (c) Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem. Eur. J. 2010, 16, 2654. (d) Topczewski, J. J.; Cabrera, P. J.; Saper, N. I.; Sanford, M. S. Nature 2016, 531, 220. (e) McNally, A.; Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J. Nature 2014, 510, 129. (f) Davis, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861. (g) White, M. C. Science 2012, 335, 807. (h) Howell, J. M.; Feng, K.; Clark, J. R.; Trzepkowski, L. J.; White, M. C. J. Am. Chem. Soc. 2015, 137, 14590. (i) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Chem. Soc. Rev. 2016, 45, 2900. (3) Choi, J.; MacArthur, A. H. R.; Brookhart, M.; Goldman, A. S. Chem. Rev. 2011, 111, 1761. (4) (a) Giri, R.; Maugel, N.; Foxman, B. M.; Yu, J-Q. Organometallics 2008, 27, 1667. (b) Baudoin, O.; Herrbach, A.; Gueritte, F. Angew. Chem., Int. Ed. 2003, 42, 5736. (c) Motti, E.; Catellani, M. Adv. Synth. Catal. 2008, 350, 565.
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(5) (a) Breslow, R.; Baldwin, S.; Flechner, T.; Kalicky, P.; Liu, S.; Washburn, W. J. Am. Chem. Soc. 1973, 95, 3251. (b) Voica, A.-F.; Mendoza, A.; Gutekunst, W. R.; Fraga, J. O.; Baran, P. S. Nat. Chem. 2012, 4, 629. (c) Hollister, K. A.; Conner, E. S.; Spell, M. L.; Deveaux, K.; Maneval, L.; Beal, M. W.; Ragains, J. R. Angew. Chem., Int. Ed. 2015, 54, 7837. (6) For moderately selective desaturation of alkyl peroxides via HAT at δ-C–H site employing stoichiometric amounts of transition metals, see: Cekovic, Z.; Dimitrijevic, L.; Djokic, G.; Srnic, T. Tetrahedron 1979, 35, 2021. (7) Parasram, M.; Chuentragool, P.; Sarkar, D.; Gevorgyan, V. J. Am. Chem. Soc. 2016, 138, 6340. (8) For a review on exogenous photosensitizer-free, visible light-induced TM-catalyzed transformations, see: Parasram, M.; Gevorgyan, V. Chem. Soc. Rev. 2017, DOI: 10.1039/c7cs00226b. (9) For a review, see: (a) Liu, Q.; Dong, X.; Li, J.; Xiao, J.; Dong, Y.; Liu, H. ACS Catal. 2015, 5, 6111. See also: (b) Bloome, K. S.; McMahen, R. L.; Alexanian, E. J. J. Am. Chem. Soc. 2011, 133, 20146. (c) Bonney, K. J.; Proutiere, F.; Schoenebeck, F. Chem. Sci. 2013, 4, 4434. (d) Venning, A. R.O.; Kwiatkowski, M. R.; Peña, J. E. R.; Lainhart, B. C.; Guruparan, A. A.; Alexanian, E. J. J. Am. Chem. Soc. 2017, 139, 11595. For a review on UVinduced Pd-catalyzed transformations involving alkyl iodides, see: (e) Sumino, S.; Fusano, A.; Fukuyama, T.; Ryu, I. Acc. Chem. Res. 2014, 47, 1563. (10) For alkyl hybrid Pd-radical intermediates capable of HAT of activated C–H bonds, see: Peacock, D. M.; Roos, C. B.; Hartwig, J. F. ACS Cent. Sci. 2016, 2, 647. (11) For a review, see: Parasram, M.; Gevorgyan, V. Acc. Chem. Res. 2017, 50, 2038. (12) (a) Parasram, M.; Iaroshenko, V. O.; Gevorgyan, V. J. Am. Chem. Soc. 2014, 136, 17926. (b) Kurandina, D.; Parasram, M.; Gevorgyan, V.; Angew. Chem., Int. Ed. DOI: 10.1002/anie.201706554. (13)For a review featuring examples beyond 1,5-HAT, see: Nechab, M.; Mondal, S.; Bertrand, M. P.; Chem. Eur. J. 2014, 20, 16034. (14) Generally, 1,5-HAT is conformationally favored (6-membered transition state) for carbon-based radicals, see ref 13. However, owning to the longer bond length of C–Si bonds, silyl methyl radicals are predisposed to adopt transition states beyond that of analogous carbon-based radicals. Thus, for T1 and T2 presented in this work, 1,6-HAT (7membered transition state) is the most preferred process, see also: (a) Koreeda, M.; Hamann, L. G. J. Am. Chem. Soc. 1990, 112, 8175 (b) Wilt, J. W.; Lusztyk, J.; Peeran, M.; Ingold, K. U. J. Am. Chem. Soc. 1988, 110, 281. (15) Classics in stereoselective synthesis; Carreira, E. M.; Kvaerno, L.; Wiley-VCH: Weinheim, Germany, 2009, 153. (16 ) See Supporting Information for details. (17) For reviews, see: (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322. (b) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116, 10035. (c) Romero, N. A.; Nicewicz, D. A. Chem. Rev. 2016, 116, 10075. (d) Staveness, D.; Bosque, I.; Stephenson, C. R. J. Acc. Chem. Res. 2016, 49, 2295. (e) Tellis, J. C.; Kelly, C. B.; Primer, D. N.; Jouffroy, M.; Patel, N. R.; Molander, G. A. Acc. Chem. Res. 2016, 49, 1429 (f) Meggers, E. Chem. Commun. 2015, 51, 3290. (g) Xie, J.; Jin, H.; Hashmi, A. S. K. Chem. Soc. Rev. 2017, 46, 5193. For selected examples, see: (h) Shu, W.; Nevado, C. Angew. Chem., Int. Ed. 2017, 56, 1881 (i) Shu, W.; Genoux, A.; Li, Z.; Nevado, C. Angew. Chem., Int. Ed. 2017, 56, 10521. (j) Hu, X.-Q.; Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2017, 56, 1960. (k) Zhang, J.; Li, Y.; Zhang, F.; Hu, C.; Chen, Y. Angew. Chem., Int. Ed .2016, 55, 1872. (l) Wang, C.; Harms, K.; Meggers, E. Angew. Chem. Int. Ed. 2016, 55, 13495. (m) Chu, J. C. K.; Rovis, T. Nature 2016, 539, 272. (n) Choi, G. J.; Zhu, Q.; Miller, D. C.; Gu, C. J.; Knowles, R. R. Nature 2016, 539, 268.
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(18) Analogous stereochemical outcome was observed upon desaturation of (-) menthol under Baran’s protocol, see ref 5b. (19) The stereoselectivity of the HAT process was investigated using cisand trans-stereoisomers of 1w-T2. For the cis-isomer, for which a quasiliner TS required for an HAT event is unlikely, the reaction produced the hydrodehalogenation by-product only. Conversely, the trans-isomer underwent HAT to produce 43% of the desaturation product. See SI for details. (20) Blanksby, S. J.; Ellison, G. B. Acc. Chem. Res. 2003, 36, 255. (21) Lumbroso, A.; Cooke, M. L.; Breit, B. Angew. Chem., Int. Ed. 2013, 52, 1890. (22) For BDEs of C–H bonds adjacent to radical centers, see: Zhang, X.M. J. Org. Chem. 1998, 63, 1872. (23) (a) Kuo, J. L.; Hartung, J.; Han, A.; Norton, J. R. J. Am. Chem. Soc. 2015, 137, 1036. (b) Hu, Y.; Shaw, A. P.; Estes, D. P.; Norton, J. R. Chem. Rev. 2016, 116, 8427. (24) The endgame, Pd-assisted H-atom elimination, occurs predominantly at the sterically less hindered site. For discussion via path A, see ref. 12a.
TOC GRAPHIC Hβ
I Si R2
Hδ
General, mild, and selective remote desaturation of alcohols at unactivated C(sp3)-H sites
O Hα
Hγ
Hε
R = i-Pr, Me The first alkyl hybrid Pd-radical HAT process at inert C(sp3)–H sites Pd-cat.
Hβ
I-Pd(I)
visible light room temp no exogenous oxidants or photosensitizers
Si R2
Hδ
3o, 2o
O Hα
Hγ
selective 1,n-HAT
Hε
H
H Si R2
n 30 examples up to 89% yield up to perfect regioselectivity
controlled
O n
H HO
H β-H elimination I-Pd(I)
5
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