Enamine-mediated addition of aldehydes to cyclic enones

Article abstract of DOI:10.1002/adsc.201000755

The O-trimethylsilylated α,α-diphenylprolinol-catalyzed addition of aldehydes to cyclic unsaturated enones is described. The apparently unusual stereochemical outcome is discussed. Copyright

Full text of DOI:10.1002/adsc.201000755

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DOI: 10.1002/adsc.201000755
Enamine-Mediated Addition of Aldehydes to Cyclic Enones
Daniele M. Scarpino Schietroma,a,b Mattia R. Monaco,a,b Valerio Visca,a,b
Susanna Insogna,a Jacob Overgaard,c,d and Marco Bellaa,b,*
a
Dipartimento di Chimica, “Sapienza” Universitꢀ di Roma, P. le Aldo Moro 5, 00185 Rome, Italy
Fax : (+39)-06-4991-3710; e-mail: marco.bella@uniroma1.it
Istituto di Chimica Biomolecolare del CNR, Universitꢀ di Roma, P. le Aldo Moro 5, 00185 Rome, Italy
Department of Chemistry, Aarhus Universitet, Langelandsgade 140, 8000 C Aarhus, Denmark
To whom enquiries concerning the X-ray structures should be addressed
b
c
d
Received: October 8, 2010; Revised: May 26, 2011; Published online: August 29, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201000755.
Abstract: The O-trimethylsilylated a,a-diphenyl-
prolinol-catalyzed addition of aldehydes to cyclic
unsaturated enones is described. The apparently un-
usual stereochemical outcome is discussed.
It should be highlighted that, in these works despite
the fact that quaternary stereocenters are also ac-
cessed, only aryl acetaldehydes are reported as sub-
strates, probably because of the occurrence of side re-
actions.[7]
Keywords: aldehydes; enones; Michael addition; or-
ganocatalysis
This work focuses on the addition reaction of alde-
hydes to the versatile electrophiles a,b’-unsaturated
b-keto esters 1 which is, to the best of our knowledge,
unreported although some recent papers describe the
addition of aldehydes to double activated Michael ac-
ceptors.[8a–e] The especially reactive enones 1a and 1b
After the landmark paper authored by List, Barbas and related systems have been already used for highly
and Lerner, reporting the discovery of the proline-cat- enantioselective metal-catalyzed reactions[9a–e] and by
alyzed intermolecular aldol reaction via enamines,[1] us, recently, in the first organocatalytic asymmetric
secondary amine activation became a well established transformation.[9f]
strategy, which has been exploited for the a-function-
Our investigation commenced by reacting electro-
alization of aldehydes with different classes of electro- phile 1a with aldehyde 2a, under various conditions
philes, such as diazodicarboxylates, halogen or oxygen (Table 1). Proline was unable to promote this reaction
sources, nitroalkenes, quinones and several others.[2] alone (entry 1); instead, the SAOc tool (combination
A reaction still elusive is the addition of aldehydes to of secondary amines I–III with tertiary amines V–
enones, which has been so far reported for the very VII)[5] afforded the desired adduct in good yield but
reactive vinyl ketones or closely related systems.[3] in low enantioselectivity (entries 2–6). Commercially
Cyclic enones, in particular, despite being exploited as available thiazolidine II, which in an early paper on
substrates in a variety of metal-catalyzed[4a–e] or orga- the aldol reaction by Barbas et al. gave one of the
nocatalyzed methodologies,[4f–i] have been employed highest enantioselectivities,[10] led to a disappointing
in the enamine addition of aldehydes only with the es- stereoinduction (entry 7). Employing thiazolidine III,
pecially reactive aryl acetaldehydes through the coop- which was the most effective catalyst in our previous
erative activation of secondary and tertiary amines work,[5] we were able to isolate adduct 3a and 3’a in
(synergic asymmetric organocatalysis or SAOc) devel- up to 82% ee (entries 8–10). Even though these re-
oped by our group.[5]
sults demonstrated once more the efficiency of cata-
Recently, Kotsuki[6a] and shortly after Carter,[6b] in- lyst combinations with respect to proline employed
dependently and simultaneously rediscovered a trans- alone, they were non-competitive, in terms of enantio-
formation originally disclosed by Yamada[6c,d] in low selectivity, when compared to the ones obtained em-
enantioselectivity for the addition of aryl acetalde- ploying O-TMS-a,a-diphenylprolinol[11] (entry 11).
hydes to acyclic enones. Intriguingly, both groups de- This catalyst was unable to promote the addition of
veloped a catalytic system based on multiple catalysis, any aldehyde to non-activated cyclic enones.[5]
a mixture of chiral acid/chiral diamine by Kotsuki and
In the light of these results, we selected catalyst IV
a combination of sulfonamide/benzylamine by Carter. to expand the scope of this specific transformation, by
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Enamine-Mediated Addition of Aldehydes to Cyclic Enones
Table 1. Screening of catalysts for the addition of capronaldehyde 2a to enone 1a.
Entry[a]
Catalyst(s)
Yield[b] [%]
ee%[c] of 3a/3a’
dr[c] of 3a/3a’
1[c]
2
I
nr
45
51
54
67
70
45
63
63
72
74
–
–
3:1
2:1
1.3:1
1:1
1.5:1
1:1.5
1.5:1
3:1
1.5:1
2:1
I+Et3N
rac/rac
À29/rac
rac/+30
rac/+34
rac/À29
rac/+20
À66/À20
À72/À30
À82/À44
93/92
3[d]
4
ent-I+QN-V
ent-I+QD-VI
ent-I+DHCp-VII
I+DHCp-VII
II+QN-V
III+QN-V
III+QD-VI
III+DHCp-VII
IV
5
6[d]
7
8[d]
9[d]
10[d]
11
[a]
Reaction conditions: 0.3 mmol 1a, 0.6 mmol 2a, 2 mL toluene; 10 mol% organocatalyst I–VII; À208C, 24–72 h.
Isolated yield.
[b]
[c]
[d]
The ee and dr values determined by CSP-GC, utilizing a b-dex column; “rac” indicates ꢀ5% ee.
Negative ee indicates the prevalent formation of the opposite enantiomer with respect to the one shown in the scheme.
analyzing several combinations of aldehydes 2 and the known bicyclo adducts 4b and 4c, the stereochem-
electrophiles 1 (Table 2). Employing the five-mem- istry of which was unambiguously determined
bered ring enone 1a, we were unable to achieve a (Scheme 1). Although in our previous work we had
good level of diastereoselectivity with any chiral or already reported the X-ray analysis of compound 4c,[5]
achiral catalyst tested, despite achieving high enantio- we characterized again both enantiomers by X-ray,
selectivity (entry 1). Instead, the reaction turned out correlating them with their HPLC traces; this con-
to be highly diastereoselective when the six-mem- firmed without any doubts our previous assign-
bered ring 1b reacted with aldehydes 2a–d (entries 2– ment.[14]
5)[12] Dihydrocinnamaldehyde 2e and aryl acetalde-
In Figure 1 is depicted the most common mode of
hydes 2f–g afforded as well the desired adducts 3g–i attack for electrophiles when O-TMS a,a-diphenyl-
in comparable stereoselectivity; these compounds had prolinol IV (intermediate A) and proline I (inter-
to be transformed into the corresponding bicycles 4a– mediate B) are employed as catalysts.[15] Armstrong
c to determine their enantiomeric excesses (entries 6– and Blackmond reported that when organic bases,
8, see Scheme 1). We also prepared seven-membered such as DBU, are used in combination with proline I,
ring enone 1c, but this compound was not reactive in (intermediate C) a reverse mode of addition (Si face
the standard conditions or even at room temperature attack) is then observed.[16]
(entry 9).[13]
In our previous work we observed that with the
To assign the relative and absolute stereochemistry electrophile 2-cyclohexen-1-one, lacking only the
of adducts 3, we correlated compounds 3h and 3i to ethoxycarbonyl group with respect to compound 1b,
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Daniele M. Scarpino Schietroma et al.
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Table 2. Addition reaction of aldehydes 2 to enones 1.
Entry[a] n,
No.
R
Yield
[%][b]
dr[c]
ee
[%][c]
1
2
1, 1a
G
1.3:1 85/87
7:1 94/nd
2, 1b CH3 (CH2)3,
2a
3
4
5
2, 1b
A
>30:1 87/nd
2, 1b CH3, 2c
2, 1b CH3 (CH2)2,
2d
3e, 86
3f, 74
4:1
10:1
93/59
>95/
nd
6[d]
2, 1b CH2Ph, 2e
3g, 76
6:1
>95/
nd
7[d]
8[d]
9[f]
2, 1b Ph, 2f
3h, 34[e]
>15:1 91/nd
>15:1 70/nd
2, 1b 4-Cl-C6H4, 2g 3i, 42[e]
3, 1c
(CH3)2CH, 2b nr
–
–
[a]
Reaction conditions: 0.3 mmol 1a–c, 0.6 mmol 2a–g, 2 mL
toluene; 10 mol% organocatalyst IV; À208C, 72 h.
Isolated yield.
[b]
[c]
The ee and dr values were determined by CSP-GC, utiliz-
ing a b-dex column.
[d]
1
The dr was determined by H NMR, the ee was deter-
Figure 1. Proposed enamine intermediates for the conjugate
addition of aldehydes to enones.
mined by HPLC employing a chiralpak IC column after
ester cleavage (NaCl, DMSO, 1408C) and decarboxyla-
tion.
[e]
[f]
Isolated overall yield after ester cleavage and decarboxy-
lation (see Scheme 1).
Reaction run at room temperature for 4 days. nr=no re-
action.
Scheme 1. Proposed mechanism for the formation of cyclohexanone derivative 3 and cycloaddition reaction leading to bicy-
cles 4.
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Enamine-Mediated Addition of Aldehydes to Cyclic Enones
for very helpful discussions. Financial support to this work
was given by University of Roma “Sapienza” (“Progetto di
Ateneo 2008–2009”).
thiazolidine-derived enamine intermediate D was at-
tacked from its Re face. Analogously to the Arm-
strong and Blackmond paper[16] we hypothesized that
the bulky ammonium ion, hindering the Re face of in-
termediate D, directed the electrophile attack on its
“free” Si face.
References
The stereochemistry found for compound 4c appa-
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mer was obtained in both the case of the thiazolidine
III-derived enamine (Figure 1, intermediate D) and as
well in the case of O-TMS a,a-diphenylprolinol IV
enamine intermediate A’. In the over 200 previously
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every electrophile would attack the enamine from its
exposed Si face (intermediate A, Schemee 1).
The observed stereochemistry is actually due to the
epimerization in DMSO at 1408C of the labile alde-
hyde a-stereocenter of compound 3’. (Scheme 1).
Considering the epimerization process, this stereo-
chemical outcome is in agreement with the one gener-
ally reported in the reactions catalyzed by IV and by
us, for thiazolidine catalyst III, and the formation of
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several aldehydes to cyclic enones in high diastereo-
and enantioselectivity. We tested the SAOc tool but
we found that in this specific case O-TMS a,a-diphe-
nylprolinol IV is more effective in terms of control-
ling the reaction stereoselectivity.
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(2 equiv.) was added at À208C. The reaction was left to
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keto ester had been totally consumed (TLC), water was
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in these cases, overall yields and enantiomeric excesses were
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Acknowledgements
Authors are grateful to Professor K. A. Jørgensen, Aarhus
University and Professor L. Mandolini, Sapienza University,
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[14] See Supporting Information for the X-ray structure
(CCDC 800934, these data can be obtained free of
charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif) and
details on the products stereochemistry determination.
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ˇ
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