Organic Letters
Letter
selectivities. The majority of dienes lead exclusively to the γ-
alkylation product; however, an ortho substituent on the arene
results in a more sluggish reaction (44% conversion in 12 h)
that furnishes approximately 10% α-coupling of the azadieno-
and Comparison to Its Internal Diene Isomer
late (entry 5). Improving reaction efficiency required the
F
omission of NaBAr , and while diastereoselectivity was lower,
4
enantioselectivity remained high (92.5:7.5 er). In all, aryl-
substituted dienes readily participate in couplings with 1 at
room temperature, affording homoallylic α-trifluoromethyl
amines 3b−j in 59−86% yield.
Alkyl-substituted terminal dienes are also effective coupling
partners; however, the Pd−DTBM-SEGPHOS-catalyzed pro-
cesses with imine 1 require elevated temperature (50 °C) to
proceed effectively (Table 3). Consequently, we also omitted
a
Table 3. Azadienolate−Alkyl Diene Coupling Scope
efficient, with the α-CF amine obtained in 48% yield, 12:1 dr,
3
and 97.5:2.5 er. Comparatively, its internal diene analogue 4
also delivers acrylate 3p with similar levels of stereoselectivity
but lower conversion.
We have explored a number of additional reaction partners
Figure 1. Limitations in Reaction Partners.
Imine 5 was tested in a coupling with diene 2a in order to
access α-difluoromethyl amines, but unfortunately, the
nucleophile undergoes complete decomposition without
alkylation. Substituted imines, such as 6, would form products
a
Reactions run under N with 0.15 mmol of diene 2 (0.75 M).
2
b
19
1
Determined by 376 MHz F NMR or 400 MHz H NMR
c
spectroscopy of the unpurified mixture. Isolated yield of purified 3.
d
e
Determined by HPLC analysis of purified 3. A 10:1 mixture of γ-
5
,6b,8
f
bearing tetrasubstituted stereogenic centers
but were
alkylation products 3k and 3k″ was formed; see ref 17. 11:1 3o:3o′.
unreactive. Other dienes were also investigated. Alcohol- and
silyl ether-containing alkyl dienes 2q and 2r lead to a complex
mixture of products, which we surmise to be a combination of
the desired γ-alkylation 3, the regiomeric α-alkylation 3′, and
the aza-Cope rearrangement products 3″, all as a mixture of
diastereomers, rather than products attributable to chain
walking.
The diene hydroalkylation with imine 1 can be performed
on a 1.0 mmol scale to furnish the α-trifluoromethyl isatin-
protected homoallylic amine 3a in 82% yield (Scheme 3).
Additionally, hydrolysis of the isatin moiety under mildly acidic
conditions delivers the free amine 7 in 77% yield.
the NaBArF additive to enable the reaction to proceed at a
higher rate. Both linear (entries 1−3) and α-branched (entries
4
amines 3k−o in 43−83% yield in up to 4:1 dr and 91:9 er.
Products derived from isomerization of the diene along the
alkyl chain (“chain walking”) prior to enolate addition could
not be detected, including with phenethyl 2k or heptadienoate
4
−5) dienes participate in the reactions, affording homoallylic
2
m. Alkyl dienes largely or solely lead to γ-alkylation of the
azadienolate, although it is notable that piperidine 2o affords
ca. 9% α product 3o′. We also observed roughly 8% of an
additional γ-alkylation product 3k″ with phenethyl diene 2k.
Homoallylic amine 3k″ bears a different connectivity with
respect to the diene-derived fragment, and a series of
experiments suggest that 3k″ is formed from the aza-Cope
Catalytic enantioselective diene hydrofunctionalization
provides an enabling route toward highly valuable chemical
building blocks that are not readily prepared by other methods.
3
Here, in combination with imine umpolung, we have shown
17
rearrangement of α-alkylation product 3k′.
that important homoallylic α-trifluoromethyl amines bearing
contiguous stereogenic centers and an internal olefin can be
accessed for the first time. Utilizing an isatin auxiliary, we have
discovered that, in contrast to other transition-metal-catalyzed
processes, palladium ligated with DTBM-SEGPHOS allows for
regioselective γ-alkylation of the derived azadienolate, generat-
Intriguingly, in the course of our alkyl diene studies, we
discovered that hexadienoate 2p (Scheme 2) undergoes diene
isomerization into conjugation with the ester prior to its
coupling with 1, furnishing the ethyl-substituted stereogenic
center of homoallylic amine 3p. The process is reasonably
C
Org. Lett. XXXX, XXX, XXX−XXX