P.G. Karmaker et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
H-bonding donor role of C9-OH group in C3, two types of structural
modifications were designed by either introduction of a second
C60-OH (C5) or protection of C9-OH with Bn (C6) and Me (C7).
However, both the additional C60-OH in C5 and protected C9-OH
in C6 and C7 gave inferior ee values (entry 11 vs 9 for C5, entry
12 vs 8 for C6, entry 13 vs 5 for C7, respectively). It indicates the
H-bond donor C9-OH predominates the stereochemistry outcome.
In addition, other derivatives like thiourea C8, urea C9 and PTC C10
were also investigated but leading to low ee values (entries 14–16).
Subsequent screening of solvent revealed CH2Cl2 was still the
best solvent with respect to both yield and enantioselectivity
(Table 1, entry 5 vs entries 17–22). However, other chlorinated
alkane solvents eroded the enantioselectivity to different extents
(entries 17 and 19) while polar CH3CN (entry 20) and less polar
toluene and THF (entries 21–22) resulted in a sharp decrease in
the enantioselectivity of 3a.
Fig. 2. The transition state to explain the enhanced enantioselectivity.
2g instead.17 A series of halogenated 1-indanone-derived b-keto
amides bearing Cl, F and Br on the benzene ring at C4, C5, or C6-
position were readily converted into the corresponding products
with enantioselectivity ranging from 82% to 86% ee (3b–g). How-
ever, electron-donating substituents such as C6-Me, C6-MeO and
C6-Ph gave a little higher 87% ee (3h–j). Furthermore, substituent
at the amide side also affected the catalytic consequences. Aniline-
derived substrates containing C40-MeO, C40-F, C40-Br, C40-CF3
groups could be transformed into the corresponding products
3k–o in excellent yields (88–96%) and good to high enantioselec-
tivities (75–86% ee) whereas the product bearing a six-membered
ring (3p) was not formed.10a,b However, the substrate scope of b-
keto amides still limited for phenyl-ring fused aromatic amides
which is benefit to the thermodynamic active enol species in the
transition state TS1, while bulky N-adamantyl amide (3q) gave
little lower 66% ee and N-benzyl amide (3r) much less 21% ee
To further optimize the results, other reaction parameters such
as the amount of catalyst loading, additives, and reaction temper-
ature were investigated. Temperature was found to have a signifi-
cant influence on the enantioselectivity. Higher reaction
temperature other than 0 °C decreased the ee value (Table 1, entry
23 vs entry 5). On the other hand, lowering the temperature from
0 °C to ꢀ20 °C and ꢀ40 °C the enantioselectivity was increased
stepwise to 91% ee (entry 25 vs entry 24) for a longer reaction time,
while further decreasing to ꢀ78 °C eroded the enantioselectivity
(entry 26). When the catalyst loading was reduced to 10 mol%,
3a was generated in low yield and reduced enantioselectivity
(entry 27). Nevertheless, more or less amount of 4 Å MS rather
than 5 mg is unbeneficial to this reaction (entries 28 and 29).
Therefore, the optimal reaction conditions are as follows:
20 mol% of C3 as the catalyst, 1.2 equiv. of cyano reagent 2e, and
stirring for 36 h in CH2Cl2 at ꢀ40 °C.
implying a possible
p-p interaction between cyano reagent and
amide (vide infra TS1).
With the optimal reaction conditions in hand, the substrate
scope was explored with results shown in Scheme 2. All these ee
values are higher than the results employing the cyano reagent
Based on the above experimental observations as well as our
previous report,17 we proposed a plausible transition state (TS1)
to explain the observed enhanced enantioselectivity with the
new cyano reagent. As illustrated in Fig. 2, cinchonine acts as a dual
functional catalyst and activates both the substrate and the cya-
nate reagent via hydrogen bonding. Firstly, the b-keto amide 1a
coordinates to the quinuclidine amine moiety of the catalyst
through H-bonding via enolate form in almost planar geometry.
Secondly, C9-OH of cinchonine connects the nitro group of 2e by
a double H-bond21 thus activating the O–CN bond. Then, the b-keto
amide 1a attacks CN preferentially from the Si face, leading to the
formation of the predominant (S)-enantiomer 3a. The OH—O dou-
ble hydrogen bonds between the nitro of 2e and C9-OH of the cat-
alyst play the crucial role to arrange the preferred TS1 more tightly
than TS2 in the case of acetyl cyano reagent 2g leading to the
improved enantioselectivity.
Conclusion
In summary, the enantioselectivity was greatly improved in the
direct electrophilic
a-cyanation of 1-indanone-derived b-keto
amides by using a new cyano transfer reagent, 1-cyanato-4-
nitrobenzene, as a result of an enhanced double-hydrogen bond-
ing. With cinchonine as the bifunctional organocatalyst, it gave a
series of
a-cyano b-keto amides in excellent yields (up to 97%)
and higher enantioselectivities (up to 91% ee) than 1-cyanato-4-
acetylbenzene.
Scheme 2. Substrate scope of the organocatalyzed a
-cyanation of b-keto amides.a
Acknowledgment
aAll reactions were performed on the scale of 0.1 mmol of the substrate with 4 Å MS
(5 mg) in CH2Cl2 (1.0 mL) at ꢀ40 °C for 36 h under an argon atmosphere. The results
are listed with isolated yields and ee values determined by chiral HPLC analysis on
Chiralpak AD-H. b30 mol% of C3 used.
The authors thank NSFC – China (21572020) for financial
support.
Karmaker, Pran Gopal
