Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of Masked Acyl Cyanide Equivalents

Article abstract of DOI:10.1021/acs.orglett.7b00449

The first enantioselective iridium-catalyzed allylic alkylation reaction of a masked acyl cyanide (MAC) reagent has been developed. The transformation allows for the use of an umpoled synthon, which serves as a carbon monoxide equivalent. The reaction proceeds with good yield and excellent selectivity up to gram scale for a wide range of substituted allylic electrophiles, delivering products amenable to the synthesis of highly desirable, enantioenriched vinylated α-aryl carbonyl derivatives.

Full text of DOI:10.1021/acs.orglett.7b00449

Letter
pubs.acs.org/OrgLett
Enantioselective Iridium-Catalyzed Allylic Alkylation Reactions of
Masked Acyl Cyanide Equivalents
J. Caleb Hethcox,‡ Samantha E. Shockley,‡ and Brian M. Stoltz*
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, 1200 East California Boulevard, MC 101-20, Pasadena, California 91125, United
States
S
* Supporting Information
ABSTRACT: The first enantioselective iridium-catalyzed allylic alkylation reaction of a masked acyl cyanide (MAC) reagent has
been developed. The transformation allows for the use of an umpoled synthon, which serves as a carbon monoxide equivalent.
The reaction proceeds with good yield and excellent selectivity up to gram scale for a wide range of substituted allylic
electrophiles, delivering products amenable to the synthesis of highly desirable, enantioenriched vinylated α-aryl carbonyl
derivatives.
ince the first report of an asymmetric iridium-catalyzed
process.4 More recently, Carreira disclosed the use of
formaldehyde N,N-dialkylhydrazone as a formyl anion equiv-
alent in iridium-catalyzed allylic alkylation reactions.5 Herein,
we disclose the first use of an acyl cyanide equivalent in
asymmetric iridium-catalyzed allylic alkylation, which formally
serves as the addition of carbon monoxide (Figure 1c, left).
As part of our ongoing research program to develop iridium-
catalyzed allylic alkylation methods,6 we became interested in
exploring the reactivity of masked acyl cyanide (MAC) reagents
as reverse-polarity nucleophiles with π-allyl electrophiles.
Following reaction with an electrophile, these umpoled
synthons, developed by Yamamoto and Nemoto,7 can be
unmasked to reveal a transient acyl cyanide intermediate, which
can be further transformed into a carboxylic acid, amide, or
ester.7,8 We envisioned that the novel application of MAC
reagents to iridium-catalyzed allylic alkylation chemistry could
provide access to highly desirable, enantioenriched vinylated α-
aryl carbonyl derivatives, which are otherwise difficult to
prepare (Figure 1c, right).9
S
allylic alkylation in 1997,1 the technology has been widely
developed for normal reactivity patterns between electrophilic
π-allyl species and nucleophilic enolate equivalents, organo-
metallic reagents, or heteroatoms (Figure 1a).2 However, the
Preliminary studies focused on the identification of a suitable
protecting group for MAC nucleophile 1 in order to achieve the
allylic alkylation reaction. Using our previously reported
conditions for iridium-catalyzed allylic alkylations with
cinnamyl-derived electrophiles as a starting point,6a,10 we
found that the reaction of either silyl ether 1a or acetate 1b
with cinnamyl carbonate (2) furnished desired products 4a and
4b, respectively, albeit in low yields (Table 1, entries 1 and 2).
However, the use of methoxymethyl ether 1c provided allylic
Figure 1. Iridium-catalyzed allylic alkylation strategies.
application of an umpolung strategy to stitch together a
formally electrophilic group and a π-allyl cation via
enantioselective iridium-catalyzed allylic alkylation remains
underexplored (Figure 1b, left).3 To date, only two examples
of reverse-polarity nucleophiles in iridium-catalyzed allylic
alkylation have been reported (Figure 1b, right). In 2008,
Helmchen showed that the extensively explored malononitrile
nucleophile could operate as a methoxy carbonyl synthon with
the subsequent application of an oxidative degradation
Received: February 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00449
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a e
,
a
Table 1. Optimization of Reaction Parameters
Scheme 1. Electrophile Substrate Scope
a
b
Reactions performed on 0.1 mmol scale. 1H NMR yield based on
c
d
internal standard. Determined by chiral HPLC analysis. Reaction run
for 48 h. TBD = 1,3,5-triazabicyclo[4.4.0]dec-5-ene.
e
alkylation product 4c in 64% yield (entry 3). Moreover, we
were pleased to find that product 4c was obtained with
excellent enantioselectivity (95% ee), obviating the need for
further optimization beyond that of conversion. Efforts to
increase the reaction conversion revealed that altering the
nucleophile-to-electrophile ratio from 1:2 to 2:1 improved the
yield to 77% with no erosion of enantioselectivity (entries 4
and 5). We observed that extending the reaction time from 18
to 48 h provided product 4c in a now synthetically useful 85%
yield and 97% ee (entry 6). Ultimately, we found that treatment
of a mixture (2:1) of nucleophile 1c and electrophile 2 with a
combination of catalytic Ir(cod)Cl·3 (4 mol %) and LiBr (200
mol %) at 60 °C delivered allylic alkylation product 4c in a high
86% yield with an exceptional 96% enantioselectivity in only 18
h (entry 7).
a
b
c
Reactions performed on 0.2 mmol scale. Isolated yield. Determined
d
by chiral HPLC or SFC analysis. Reaction run for 36 h at 50 °C.
With the optimized conditions identified, the substrate scope
of the enantioselective umpolung reaction was explored
(Scheme 1).11 Our investigation began by probing the effects
of electronics on reaction yield and selectivity. Gratifyingly, we
observed that para-substituted aryl electrophiles bearing both
electron-withdrawing (−Br, −CF3, −F) and electron-donating
(−OMe) groups furnished products 6a−d with consistently
excellent enantioselectivities (>95% ee). While products 6a
(−Br) and 6d (−OMe) were obtained in high yield (>94%
yield), diminished yields (58% and 69% yield, respectively)
were obtained for the more electron-poor products 6b (−CF3)
and 6c (−F). Further examination of electrophile electronics
revealed that meta-Cl-substituted 6e, as well as polyalkoxylated
6f and 6g, were each furnished in good yields (>81%) and high
enantioselectivities (92−98% ee), despite varying electronics.
Studies involving sterically demanding substrates showed that
products 6h (−2-Np) and 6i (−ortho-Me) could be provided
with good selectivities (92% and 89% ee, respectively), albeit in
moderate yields (41% and 65%, respectively). Additionally, we
were pleased to discover that pyridine 6j, furan 6k, and
thiophene 6l could each be afforded with excellent
enantioselectivities (90−96% ee) and in moderate to high
yields (73−94%). To demonstrate the synthetic utility of this
method, a preparatory scale (4 mmol) reaction was performed
(Scheme 2). Using cinnamyl carbonate (2), both the yield and
enantioselectivity of the reaction were unchanged from those
obtained at 0.1 mmol scale.
Scheme 2. Preparatory Scale Reaction
this reaction diverges from the normal reactivity patterns
employed in all but two of the previously reported iridium-
catalyzed allylic alkylations and is the first report of a carbon
monoxide synthon in iridium-catalyzed allylic alkylation.
Critical to the success of this new reaction is the identity of
the methoxymethyl protecting group on the MAC reagent. The
developed methodology proceeds with moderate to excellent
yields (up to 95%) and high levels of enantioselectivity (up to
98% ee) up to gram scale for a wide range of aryl- and
heteroaryl-substituted allylic electrophiles. Furthermore, MAC
adducts bearing resemblance to compound 4c have been
transformed into acids, amides, and esters by unmasking the
alkoxy malononitrile moiety.7,8 Thus, this methodology serves
as an entry to enantioenriched vinylated α-aryl carbonyl
derivatives. Further explorations to expand the scope of this
chemistry to include additional electrophile classes are currently
underway and will be reported in due course.
In summary, we have developed the first enantioselective
iridium-catalyzed allylic alkylation reaction of masked acyl
cyanide (MAC) reagents. The umpolung strategy showcased in
B
DOI: 10.1021/acs.orglett.7b00449
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
7195−7196. (c) Nemoto, H.; Ma, R.; Ibaragi, T.; Suzuki, I.; Shibuya,
M. Tetrahedron 2000, 56, 1463−1468. (d) Yamatsugu, K.; Kanai, M.;
Shibasaki, M. Tetrahedron 2009, 65, 6017−6024. (e) Yang, K. S.;
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00449.
Nibbs, A. E.; Turkmen, Y. E.; Rawal, V. H. J. Am. Chem. Soc. 2013, 135,
̈
16050−16053. (f) Yang, K. S.; Rawal, V. H. J. Am. Chem. Soc. 2014,
136, 16148−16151. (g) Kagawa, N.; Nibbs, A. E.; Rawal, V. H. Org.
Lett. 2016, 18, 2363−2366.
Experimental procedures, spectroscopic data (1H NMR,
(9) (a) Murphy, K. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125,
4690−4691. (b) Trost, B. M.; Xu, J. J. Am. Chem. Soc. 2005, 127,
17180−17181. (c) Yan, S.-S.; Liang, C.-G.; Zhang, Y.; Hong, W.; Cao,
B.-X.; Dai, L.-X.; Hou, X.-L. Angew. Chem., Int. Ed. 2005, 44, 6544−
6546. (d) Zheng, W.-H.; Zheng, B.-H.; Zhang, Y.; Hou, X.-L. J. Am.
Chem. Soc. 2007, 129, 7718−7719. (e) Lundin, P. M.; Esquivias, J.; Fu,
G. C. Angew. Chem., Int. Ed. 2009, 48, 154−156. (f) Lou, S.; Fu, G. C.
J. Am. Chem. Soc. 2010, 132, 1264−1266. (g) Cherney, A. H.;
Kadunce, N. T.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 7442−
7445. (h) Poremba, K. E.; Lee, V. A.; Sculimbrene, B. R. Tetrahedron
2014, 70, 5463−5467. (i) Liu, Y.; Virgil, S. C.; Grubbs, R. H.; Stoltz, B.
M. Angew. Chem., Int. Ed. 2015, 54, 11800−11803.
13C NMR, IR, HRMS), and SFC/HPLC data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: stoltz@caltech.edu.
ORCID
Brian M. Stoltz: 0000-0001-9837-1528
Author Contributions
‡J.C.H. and S.E.S. contributed equally.
Notes
(10) As in ref 6a, LiBr was found to improve the regioselectivity of
the allylic alkylation reaction. The use of 200 mol % (in comparison to
100 mol % as in ref 6a) provided consistently higher yields of the
branched product.
The authors declare no competing financial interest.
(11) The optimized reaction conditions failed to provide high
regioselectivities when aliphatic-substituted allylic electrophiles were
employed.
ACKNOWLEDGMENTS
■
The NIH-NIGMS (R01GM080269) and Caltech are thanked
for support of our research program. Additionally, J.C.H. thanks
the Camille and Henry Dreyfus postdoctoral program in
Environmental Chemistry, and S.E.S. thanks the NIH-NIGMS
for a predoctoral fellowship (F31GM120804). Dr. Mona
Shahgholi (Caltech) and Naseem Torian (Caltech) are thanked
for mass spectrometry assistance. Dr. Scott Virgil (Caltech) is
thanked for assistance with instrumentation.
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DOI: 10.1021/acs.orglett.7b00449
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