Diastereoselective Allylation of Aldehydes by Dual Photoredox and Chromium Catalysis

Article abstract of DOI:10.1021/jacs.8b08052

Herein, we report the redox-neutral allylation of aldehydes with readily available electron-rich allyl (hetero-) arenes, β-alkyl styrenes and allyl-diarylamines. This process was enabled by the combination of photoredox and chromium catalysis, which allowed a range of homoallylic alcohols to be prepared with high levels of selectivity for the anti diastereomer. Mechanistic investigations support the formation of an allyl chromium intermediate from allylic C(sp³)-H bonds and thus significantly extends the scope of the venerable Nozaki-Hiyama-Kishi reaction.

Full text of DOI:10.1021/jacs.8b08052

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Communication
Diastereoselective Allylation of Aldehydes
by Dual Photoredox and Chromium Catalysis
Jonas Luca Schwarz, Felix Schäfers, Adrian Tlahuext-Aca, Lukas Lückemeier, and Frank Glorius
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08052 • Publication Date (Web): 14 Sep 2018
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Diastereoselective Allylation of Aldehydes by Dual Photore-
dox and Chromium Catalysis
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J. Luca Schwarz,‡ Felix Schäfers,‡ Adrian TlahuextꢀAca, Lukas Lückemeier and Frank Glorius*
OrganischꢀChemisches Institut, Westfälische WilhelmsꢀUniversität Münster, Corrensstraße 40, 48149 Münster, Germany
Supporting Information Placeholder
ABSTRACT: Herein, we report the redoxꢀneutral allylation of
aldehydes with readily available electronꢀrich allyl (heteroꢀ)
arenes, βꢀalkyl styrenes and allylꢀdiarylamines. This process was
enabled by the combination of photoredox and chromium catalyꢀ
sis, which allowed a range of homoallylic alcohols to be prepared
with high levels of selectivity for the anti diastereomer. Mechaꢀ
nistic investigations support the formation of an allyl chromium
3
intermediate from allylic C(sp )–H bonds and thus significantly
extends the scope of the venerable NozakiꢀHiyamaꢀKishi reaction.
The allylation of carbonyls is an important class of reaction in
3
3
1
organic synthesis for the formation of C(sp )–C(sp ) bonds. The
resulting homoallylic alcohol products are valuable and versatile
building blocks, which are frequently employed in natural product
2,3
synthesis. Among the important carbonyl allylation protocols of
1
Brown, Roush, Leighton and Krische, one of the most well estabꢀ
lished methods for the allylation of aldehydes is the Nozakiꢀ
4
HiyamaꢀKishi (NHK) reaction (Figure 1a). This chromiumꢀ
mediated reaction proceeds with excellent chemoselectivity for
aldehydes over otherwise reactive ketones or esters and furtherꢀ
more selectively forms the anti diastereomer independent of the
original allyl C–C double bond geometry. The NHK reaction has
therefore become a powerful synthetic tool in the synthesis of
5
complex bioactive molecules. However, the generation of toxic
chromium waste in stoichiometric amounts remains a concern.
This problem has inspired elegant work by Fürstner and others
Figure 1. (a) Diastereoselective allylation of aldehydes with allyl
chromium species (NozakiꢀHiyamaꢀKishi reaction). (b) (Nonꢀ
diastereoselective) alkylation of carbonyls via photoredox catalyꢀ
sis. (c) This work: Diastereoselective allylation of aldehydes by
dual photoredox and chromium catalysis.
6
7
on the design of catalyticꢀinꢀchromium NHKꢀtype reactions.
These catalytic processes typically utilize allylic halides in comꢀ
bination with a silyl Lewis acid and an excess of manganese as a
terminal reductant to afford silylꢀprotected homoallylic alcohols.
From a strategic and atom economic viewpoint, the direct funcꢀ
tionalization of more readily available allylic C–H bonds in a
catalytic redoxꢀneutral process would therefore be highly desiraꢀ
ble.
Considering this, and given the success of the combination of
photoredox and transition metal catalysis for C–C and C–X bond
14
formation, we questioned if a similar dual catalytic approach
could be developed to provide facile access to allyl chromium
intermediates and thus allow the chemoꢀ and diastereoselective
allylation of aldehydes from versatile radical precursors (Figure
In recent years, the functionalization of C–H bonds by photoreꢀ
8
dox catalysis has received widespread attention, yet the use of
1
2
c). We envisaged the dual catalytic process illustrated in Figure
. First, this process would initiate by photoexcitation of a suitaꢀ
carbonyls as coupling partners in this context remains underdeꢀ
veloped. Two major pathways for the C–C bond formation beꢀ
tween alkyl radicals and carbonyls can be distinguished (Figure
III
ble photocatalyst, such as [Ir(dF(CF )ppy) (dtbbpy)][PF ] (Ir ,
3
2
6
9,10
dF(CF )ppy = 2ꢀ(2,4ꢀdifluorophenyl)ꢀ5ꢀ(trifluoromethyl)pyridine,
3
1
b). First, alkyl radicals can add directly to C–O double bonds.
dtbbpy = 4,4'ꢀdiꢀtertꢀbutylꢀ2,2'ꢀbipyridine), which would be transꢀ
However, this step is reversible and thermodynamically unfaꢀ
voured, thus limiting the applicability of this process, especially
III
*
III II
ferred to its highly oxidizing exited state *Ir (E1/2 ( Ir /Ir ) =
15
11
1.21 V vs. SCE in MeCN). Reductive quenching of the excited
Ir photocatalyst by an allyl (heteroꢀ) arene 1 would generate an
aryl radical cation 1 and the reduced Ir photocatalyst. This
for intermolecular reactions. Second, aromatic carbonyls can be
III
*
reduced to longꢀlived ketyl radicals, which can undergo radicalꢀ
·
+
II
1
2
radical coupling with suitable alkyl radicals. Importantly, both
13
cation could then be readily deprotonated to generate an allyl
mechanistic pathways proceed without diastereocontrol.
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Figure 4. Mechanistic Analysis. Isolated yields. (a) Radical trapꢀ
ping experiment adding TEMPO to standard conditions. (b) Exꢀ
cluding the involvement of ketyl radicals by a radical clock experꢀ
iment using 2,2ꢀdimethylcyclopropylcarbaldehyde (4s).
Figure 2. Proposed catalytic cycle. The anti selectivity of this
reaction can be explained by the illustrated Zimmerman Traxler
transition state.
trapping agent TEMPO (2,2,6,6ꢀtetramethylpiperidinyloxyl) also
completely inhibited the reaction, thus suggesting that a radical
pathway is operative (Figure 4a). A radical clock experiment
using 2,2ꢀdimethylcyclopropylcarbaldehyde (4s) was conducted
to rule out the involvement of ketyl radicals, which would be
expected in a radicalꢀradical coupling mechanism (Figure 4b). No
ring opened products could be detected and the desired homoalꢀ
lylic alcohol 6as was isolated in 81% yield as a mixture of diaꢀ
stereomers, suggesting that ketyl radicals are not involved in this
reaction. Finally, the quantum yield of this reaction was deterꢀ
mined to be 0.049 by chemical actinometry.
Figure 3. Standard reaction conditions.
II
radical 2. Radical capture with lowꢀvalent L Cr would then form
n
III
LnCr allyl species 3a and 3b. At this point, we expected that the
Next, the generality of this allylation protocol was evaluated
19
linear regioisomer 3a would react with an aldehyde 4 via a sixꢀ
(
Figure 5). Various allylꢀindoles as well as Nꢀallylꢀcarbazole,
membered Zimmerman Traxler transition state to generate the
were reactive and afforded the desired products (6aa–da) in high
yields and with excellent diastereoselectivities. Notably, even free
N–H bonds of indoles (6da) and halide substituents (6ba) were
tolerated, which could be used for subsequent functionalization.
The anti configuration of the products was unambiguously asꢀ
1
6
chromium alkoxide 5 in an anti selective fashion. Subsequent
chromium alkoxide hydrolysis would generate the desired unproꢀ
III
tected homoallylic alcohol product 6 and highꢀvalent L Cr .
n
Finally, both catalytic cycles would be closed by single electron
II
III 17
2
0
transfer between the reduced Ir photocatalyst and L Cr .
n
signed by Xꢀray crystallographic analysis of product 6ca. The
scope was further extended to simple allyl benzenes. Allyl benꢀ
zene derivatives are attractive targets as they are part of the pheꢀ
nylpropanoid natural product family and have been used as preꢀ
Herein, we report the successful realization of the combination
of photoredox and chromium catalysis to enable the redoxꢀneutral
allylation of aldehydes with unfunctionalized allyl (heteroꢀ)
arenes, βꢀalkyl styrenes and allylꢀdiarylamines. The reaction
forms the anti diastereomer selectively and, by avoiding external
silyl Lewis acids, allows direct access to unprotected alcohols.
This method could be used for the selective allylation of aliphatic
and aromatic aldehydes in the presence of ketones and esters. The
mild reaction conditions also tolerate a broad range of functional
groups as demonstrated through substrate scope investigations and
an additiveꢀbased screen.
21
cursors in the synthesis of insecticides. We first tested methyl
eugenol as the substrate in this reaction and to our delight, the
desired product 6ea was obtained in 95% yield as a single diaꢀ
stereomer. Encouraged by these results, Estragole was then subꢀ
jected to a modified reaction protocol, in which a more oxidizing
photocatalyst [Ir(dF(CF )ppy) (bpy)][PF ] (bpy = 2,2'ꢀbipyridine)
3 2 6
III II
22
(E1/2 (*Ir /Ir ) = 1.32 V vs. SCE) was required to afford the
desired product 6fa in 27% yield as a single diastereomer. Given
the success of methyl eugenol in this transformation, we wonꢀ
dered if βꢀalkyl styrenes could also be used in this allylation
protocol. These would be attractive precursors as they can be
easily synthesized from the corresponding carbonyl compound via
classical olefination procedures and would give rise to the same
allyl radical intermediates after the oxidation and deprotonation
sequence. First, a commercially available cis/trans mixture of
methyl isoeugenol was employed to test this proposal. To our
delight, the allylated product 6ea was obtained exclusively in 83%
yield as a single diastereomer, supporting our hypothesis. The
scope was further extended to other alkoxylated βꢀmethyl styrenes
Our studies towards the designed Ir/Cr dual catalytic approach
began by reacting Nꢀallylꢀindole (1a) and 4ꢀfluorobenzaldehyde
II
(
4a) in the presence of a base and Cr complexes under visibleꢀ
lightꢀmediated photocatalytic conditions. Pleasingly, after short
optimization studies, a mixture of [Ir(dF(CF )ppy) (dtbbpy)][PF ],
3
2
6
CrCl and Li CO proved optimal and the desired product 6aa
2
2
3
could be obtained in 76% isolated yield with an 11:1 diastereoꢀ
meric ratio (Figure 3). Importantly, pyridine can also be used
instead of Li CO3 to enable homogenous reaction conditions.
2
Having established the optimized reaction conditions, we sought
to validate our envisioned mechanistic proposal. First, control
experiments revealed that no product was formed in the absence
of the photocatalyst or light irradiation. However, in the absence
of the chromium catalyst, low levels of background reactivity
were detected (<25% yield), but this produced only a 1:1 mixture
(
6ga–ia), including benzyloxy substituents that can be readily
removed to yield the free hydroxy groups. Next, we examined
whether 1,2ꢀamino alcohols, which are important structures found
23
in a number of pharmaceuticals and natural products, could be
18
prepared using our method starting from readily available allylic
amines. We were pleased to find that Nꢀallylꢀdiarylamines were
indeed reactive, affording the desired products 6ja–ma in high
of diastereomers, suggesting that organochromium intermediates
formed during the course of the reaction. Next, SternꢀVolmer
quenching studies proved that Nꢀallylꢀindole (1a) quenches the
III
excited state of the Ir photocatalyst. The addition of the radicalꢀ
2
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Figure 5. Substrate Scope. Isolated yields. Diastereomeric ratios were determined by H or F NMR spectroscopy of the crude reaction
mixture. For detailed experimental procedures see the Supporting Information. (a) Performed with [Ir(dF(CF )ppy) (bpy)][PF ] (2 mol%).
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Ar = 4ꢀFꢀC H .
6
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yields with excellent diastereoselectivies. In this regard, the forꢀ
mation of geminal disubstituted terminal alkenes was also
achieved (6ma).
multiple different carbonyl moieties, was also employed in this
allylation protocol. Pleasingly, the ketone and ester groups did not
affect the reaction and the desired product 6lr was isolated in 68%
yield. Additionally, as enantioselective NHKꢀtype allylations are
Having established the scope of the allyl (heteroꢀ) arenes, the
substrate scope concerning the carbonyl substituent was examꢀ
ined. Aliphatic and aromatic aldehydes were equally suitable.
Primary (6lb, lc) and secondary (6ld–lg) aliphatic aldehydes all
afforded the desired products in high yield with excellent diaꢀ
stereoselectivity. However, tertiary aliphatic aldehydes were
unreactive, likely due to steric reasons. For aromatic aldehydes
many functional groups, including halides (6la, lh–lj), trifluoroꢀ
methyl groups (6lk) and ethers (6lm), were tolerated. It is noteꢀ
worthy that even sterically demanding substituents like oꢀbromo
5
well studied and to examine future developments of our dual
catalytic approach, preliminary studies towards an enantioselecꢀ
tive variant were conducted. To our delight, when enantiopure
7c
Nakada’s carbazoleꢀbased bisoxazoline ligand was tested under
our reaction conditions with Nꢀallylꢀdiphenylamine and 4ꢀ
fluorobenzaldehyde (4a), a moderate enantiomeric excess (20%
ee) for product 6la was obtained (see the Supporting Information
for details). Although modest, these results clearly demonstrate
the feasibility of an enantioselective protocol, which remains the
focus of ongoing work.
(
6lp) and oꢀmethyl (6lo) did not affect the performance and selecꢀ
tivity of the reaction. In this context, the scalability of this method
was also tested. Using 4ꢀiodobenzaldehyde and Nꢀallylꢀ
diphenylamine under the standard reaction conditions, we were
able to isolate 1.5 g (86% yield, >19:1 d.r.) of the desired homoalꢀ
lylic alcohol product 6lj in a single batch. As reported previously
for chromium allyl species, the reaction proved to be highly
chemoselective for aldehyde functionalization; other carbonyls
did not afford the homoallylic alcohol products. To highlight this
high chemoselectivity, an Epiandosterone derivative, containing
Finally to highlight the robustness of this allylation protocol, an
additiveꢀbased screen was performed (see Supporting Information
for details). From this screen, 13 out of 14 additives had only
little influence on the yield, illustrating the functional group tolerꢀ
ance of this mild reaction protocol. Importantly, nitrile and ketone
additives were also recovered quantitatively.
24
In conclusion, we have disclosed a mild, redoxꢀneutral and
scalable method for the diastereoselective allylation of aldehydes
3
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with unfunctionalized allyl (heteroꢀ) arenes enabled by the comꢀ
bination of photoredox and chromium catalysis. Mechanistic
investigations support the involvement of a chromium allyl speꢀ
cies that reacts via a sixꢀmembered transition state with the aldeꢀ
hyde. A variety of readily available allyl arenes were reactive,
including indoles, carbazoles and electronꢀrich allyl benzenes.
Additionally, the substrate scope was extended for the αꢀC(sp3)–
H functionalization of βꢀalkyl stryrenes and allylꢀdiarylamines.
Aliphatic and aromatic aldehydes are both equally reactive and
selective and can be functionalized in the presence of ketones and
esters. To the best of our knowledge, this work represents the first
example of dual photoredox and chromium catalysis. Overall, we
expect this approach to be widely employed in selective aldehyde
functionalizations.
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(
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ASSOCIATED CONTENT
Supporting Information
(
photoredox catalysis, see: (a) Wang, C.ꢀS.; Dixneuf, P. H.; Soulé, J.ꢀF.
Chem. Rev. 2018, 118, 7532. (b) Nakajima, K.; Miyake, Y.; Nishibayashi,
Y. Acc. Chem. Res. 2016, 49, 1946. (c) Fabry, D. C.; Rueping, M. Acc.
Chem. Res. 2016, 49, 1969. (d) Huang, L; Rueping, M. Angew. Chem. Int.
Ed. 2018, 57, 10333. (e) Loh, Y. Y.; Nagao, K.; Hoover, A. J.; Hesk, D.;
Rivera, N. R.; Colletti, S. L.; Davies, I. W.; MacMillan, D. W. C. Science
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental and computational details (PDF)
Crystallographic Data for 6ca (CIF)
2
017, 358, 1182. (f) Le, C.; Liang, Y.; Evans, R. W.; Li, X.; MacMillan,
AUTHOR INFORMATION
Corresponding Author
D. W. C. Nature 2017, 547, 79. (g) Shaw, M. H.; Shurtleff, V. W.; Terrett,
J. A.; Cuthbertson, J. D.; MacMillan, D. W. C. Science 2016, 352, 1304.
(h) Jeffrey, J. L.; Terrett, J. A.; MacMillan, D. W. C.; Science 2015, 349,
1
532. (i) Romero, N. A.; Margrey, K. A.; Tay, N. E.; Nicewicz, D. A.;
*glorius@uniꢀmuenster.de
Science 2015, 349, 1326. (j) McManus, J. B.; Nicewicz, D. A. J. Am.
Chem. Soc. 2017, 139, 2880. (k) Margrey, K. A.; Levens, A.; Nicewicz,
D. A.; Angew. Chem. Int. Ed. 2017, 56, 15644. (l) McManus, J. B.;
Onuska, N. P. R.; Nicewicz, D. A. J. Am. Chem. Soc. 2018, 140, 9056.
(m) Margrey, K. A.; Czaplyski, W. L.; Nicewicz, D. A.; Alexanian, E. J.
J. Am. Chem. Soc. 2018, 140, 4213. (n) Mukherjee, S.; Maji, B.; Tlahuextꢀ
Aca, A.; Glorius, F. J. Am. Chem. Soc. 2016, 138, 16200.
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interests.
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T. J. Org. Chem. 1987, 52, 3243. (c) Sanderson, J. R.; Lin, J. J.; Duranꢀ
leau, R. G.; Yeakey, E. L.; Marquis, E. T. J. Org. Chem. 1988, 53, 2859.
ACKNOWLEDGMENT
th
Dedicated to Prof. Holger Butenschön on the occasion of his 65
birthday. Generous thank to the Alfried Krupp von Bohlen and
Halbach Foundation (J.L.S.) and the Deutsche Forschungsgeꢀ
meinschaft (Leibniz Award) for financial support. We thank Max
Lübbesmeyer and Andre Kemna for experimental support, Mario
Wiesenfeldt, Dr. Michael James, Santanu Singha and Satobhisha
Mukherjee for helpful discussion, and Dr. Constantin G. Daniliuc
and Birgit Wibbeling (all WWU Münster) for the Xꢀray crystalloꢀ
graphic analysis.
(
d) Oyama, M. J. Org. Chem. 1965, 30, 2429. (f) Kawamoto, T.; Fukuyaꢀ
ma, T.; Ryu, I. J. Am. Chem. Soc. 2012, 134, 875.
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(
(
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(17) Another possible mechanism, involving oxidative quenching of
the photocatalyst could not be ruled out. For details see the Supporting
Information.
1
2
3
4
5
6
7
8
9
(18) For a discussion about the background reactivity, see the Supꢀ
porting Information.
(19) For selected examples of (enantioselective) carbonyl anti (αꢀ
amino)allylation and anti (αꢀaryl)allylation, see: (a) Skucas, E.; Zbieg, J.
R.; Krische, M. J. J. Am. Chem. Soc. 2009, 131, 5054. (b) Zbieg, J. R.;
McInturff, E. L.; Krische, M. J. Org. Lett. 2010, 12, 2514. (c) Zhang, W.;
Chen, W.; Xiao, H.; Krische, M. J. Org. Lett. 2017, 19, 4876. (d) Cabrera,
J. M.; Tauber, J.; Zhang, W.; Xiang, M.; Krische, M. J. J. Am. Chem. Soc.
2
018, 140, 9392.
20) CCDC 1858120 (6ac) contains the supplementary crystallographꢀ
ic data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
21) Barros, J.; SerraniꢀYarce, J.; Chen, F.; Baxter, D.; Venables, B.
(
1
1
1
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1
1
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0
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(
J.; Dixon, R. A. Nat. Plants 2016, 2, Article number 16050. (b) Vogt, T.
Molecular Plant 2010, 3, 2.
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D. R. Chem. Rev. 1996, 96, 835.
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9
154. (b) Collins, K. D.; Glorius, F. Nat. Chem. 2013, 5, 597.
O
Ir
Cr
OH
H
R
R
+
n
L Cr
R
O
allyl radical
precursor
aldehyde
homoallylic
alcohol
Zimmerman Traxler
Transition State
R = electron-rich aryl,
heteroaryl, amino
3
ꢀ
ꢀ
C(sp )−H bond functionalization
ꢀ high chemo- and diastereoselectivity
ꢀ first example of dual photoredox/Crcatalysis
facile access to allyl chromium intermediates
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