N-heterocyclic carbene-catalyzed Ireland-Coates claisen rearrangement: Synthesis of functionalized β-lactones

Article abstract of DOI:10.1021/ja310449k

The N-heterocyclic carbene (NHC)-catalyzed Claisen rearrangement of hybrid Ireland-Coates structures has been achieved, allowing the stereoselective synthesis of highly functionalized β-lactones. The reaction proceeds with high diastereoselectivity (>20:1

Full text of DOI:10.1021/ja310449k

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Communication
N-Heterocyclic Carbene Catalyzed Ireland-Coates Claisen
rearrangement: Synthesis of functionalized #-lactones
Lisa Candish, and David William Lupton
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja310449k • Publication Date (Web): 17 Dec 2012
Downloaded from http://pubs.acs.org on December 17, 2012
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Journal of the American Chemical Society
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N-Heterocyclic Carbene Catalyzed Ireland-Coates Claisen
Rearrangement: Synthesis of functionalized β-Lactones
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Lisa Candish and David W. Lupton*
School of Chemistry, Monash University, Clayton 3800, Victoria, AUSTRALIA.
Supporting Information Placeholder
Previously reported
Ar
Detailed herein
Ar
ABSTRACT: The NHC-catalyzed Claisen rearrangement
of hybrid Ireland-Coates structures has been achieved
allowing the stereoselective synthesis of highly function-
alized β-lactones. The reaction proceeds with high dia-
stereoselectivity (>20:1) affording a diverse range of
β−lactone fused cyclopentanes. Mechanistic studies are
detailed.
N
N
6
6
Ireland type acceleration at C2.
Coates type acceleration at C4.
New avenues for reaction discovery?
1
1
4
4
X
O
O
2
2
N
N
R
O
O
OR
Ar
I
III
Formal (3 + 2) annulation via Ireland/Coates-Claisen
Ar
O
OR
O
N
O
H
O
(1)
N
O
O
OR
VI
II
1
Ar
acyl anion/enolate chemistry?
Ar
O
Ar
O
N
6
N
Catalysis of the Claisen rearrangement presents oppor-
tunities in reaction discovery that are only beginning to
be realized.1 Recently, N-heterocyclic carbene (NHC)
catalyzed Claisen rearrangements have been reported2
via hemiacetal intermediates analogous to those reported
by Coates.3 While consensus on the mechanism is yet to
be established,4 the transformation is general,5 and often
enantioselective. Surprisingly, while an active area of
research, to date only transformations involving Coates
type intermediates (i.e. I) are known. As part of studies
into the chemistry of α,β-unsaturated acyl azoliums (II)
we were interested in Claisen rearrangements that in
addition to C4 (Coates) acceleration are activated at C2
(Ireland),6 as in intermediate III. It was postulated that
such a reaction (i.e. IV→V) should be orders of magni-
tude faster than earlier NHC catalyzed Claisen rear-
rangements,2,4-5 thereby providing access to previously
unattainable reaction designs (Figure 1). For example,
might a rapid Claisen rearrangement allow cascade reac-
tions7 using bifunctional enolate VI, without competing
aldol, or acyl anion equivalent formation? Herein we
report the realization of this strategy with the NHC-
catalyzed synthesis of highly functionalized β-lactones 1
by a Claisen rearrangement, aldol, β-lactonization8 reac-
tion cascade (eq. 1).
1
H
4
H
O
O
2
N
N
O
O
OR
OR
Ar
Ar
IV
V
Ireland type acceleration (C2)
Coates type acceleration (C4)
Figure 1. Reaction design.
strategy was trialed with cyclopropane 2a, and acyl fluo-
ride 3a, using 10 mol% IMes (A1), diastereomerically
pure cyclopentane 1a formed, as determined by 1H-
NMR, however ester 4a was the major product, presum-
ably as a result of competing proton transfer (Table 1,
entry 1). Solvation of the KCl derived from NHC genera-
tion11 using THF improved the yield of 1a, however 4a
remained a significant byproduct (Table 2, entry 2). Im-
idazolium derived NHCs free from salt byproducts have
previously improved related transformations,12 although
this was not the case with this reaction (Table 1, entry 3).
Further acceleration of the Claisen, and elimination of
competing side reaction, was attempted by replacing the
ethyl ester (2a) with progressively more electron rich
aromatics, culminating in p-CH3OC6H4 2d. Gratifyingly
this improved the yield of 1 to 89% (Table 1, entries 4-6).
In all cases cyclopentane 1 formed as a single diastere-
omer with relative stereochemistry assigned by nOe.13
The reaction was sensitive to the catalyst, with IPr (A2)
increasing formation of aldehyde 4d, and decreasing
stereoselectivity, 1d now formed as a 1:1 mixture with
1d' (vide infra) (Table 1, entry 7). Finally chiral triazoli-
um (B1 and 2) and imidazolium (C)14 derived catalysts
Studies commenced using donor-acceptor cyclopro-
panes (i.e. 2a) as precursors to VI.9 It was proposed that
acyl azolium formation from acyl fluorides (i.e. 3a)
should trigger desilylation and retro-aldol reaction of the
cyclopropane to provide VI.10 When this
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Table 2. Scope of the formal (3 + 2) annulation.a,b
Page 2 of 5
failed to convert the starting materials (Table 1, entry 8-
1
2
3
4
5
6
7
8
10).15
F
R2
10 mol% A1,
4Å sieves, toluene,
!78"rt, 14h
O
R2
O
Table 1. Optimization studies
OAr
O
OAr
O
(3)
TMSO
Mes
N
O
F
Ph
R1 R1
(±)-1
R1
(±)-2
R1
O
Ph
O
N
10 mol% cat.
solvent,
! 78 ºC rt, 14h
Mes
O
3
A1
OR
O
OR
OR
O
TMSO
(2)
R
2a, R = Et
O
O
O
3a
b, R = p! BrC6H4
c, R = C6H5
d, R = p! CH3OC6H4
O
O
O
3
(±)-2a-d
4
(±)-1
O
O
O
O
O
O
O
9
Ar
R
Mes
OCH3
OCH3
OCH3
N
N
10
11
12
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O
N
O
N
R
N
N
N
(±)-1d, R= H, 89%
CH3
(±)-1i, 84%
(±)-1j, 41%
(±)-1e, R = o-CH3O, 81%
(±)-1f, R = p-CH3O, 93%
(±)-1g, R = p-Br, 69%
(±)-1h, R = p-NO2, 65%
B1, Ar = C6F5
B2, Ar = Ph
A1, IMes: R = 2,4,6-(CH3)3C6H2
A2, IPr: R = 2,6-(iPr)2C6H3
O
O
C
entry cata
solvent/additive
2
1:4b
Yield of 1c,d
OCH3
OCH3
1
A1
A1
A1f
A1
A1
A1
A2
B1
B2
C
Toluene
2a 1:2
30e (>20:1 dr)
41 (>20:1 dr)
33 (>20:1 dr)
43 (>20:1 dr)
78 (>20:1 dr)
O
O
O
H3CO
O
O
Ph
O
2
THF/4Å sieves
"
"
1:1
1:1
O
O
OCH3
O
O
OCH3
O
R
H3C CH3
O
3
"
"
"
"
"
"
"
"
H3C CH3
O
(±)-1l, 47%
Ar
(±)-1m, 79%
4
2b 1:1
2c 5:1
O
Ar
H3CO
O
H3CO
(±)-1a, R = Et, 41%
5
(±)-1b, R = p-BrC6H4, 43%
(±)-1c, R = Ph, 78%
(±)-1k, R =o,p-(CH3O)2C6H3, 75%
O
O
O
OCH3
OCH3
O
6
7
2d 25:1 89 (>20:1 dr)
O
"
"
"
"
2:1
62 (1:1 dr)
(±)-1n, Ar = Ph, 65%
(±)-1o, Ar = p-CH3OC6H4, 78%
(±)-1p, Ar = Ph, 66%
(±)-1q, Ar = p-CH3OC6H4 78%
8
NRg
NRg
NRg
-
-
-
aIsolated yield following column chromatography bA1 generat-
ed from the imidazolium salt with KHMDS
9
10
providing LiCl rather than KCl as the salt byproduct.
This modification resulted in significant erosion in yield
(eq. 4), a result consistent with anion accelerated Claisen
rearrangement. Further support for turnover limiting
Claisen was observed by determining the secondary ki-
netic isotope effects (SKIE) α- and β-to the carbonyl (eq.
5). While internal completion studies can give ambigu-
ous results,17b cyclopropyl ring opening should be rapid,9
therefore labeled substrate will be involved in the turn
aNHC generated using equimolar KHMDS bDetermined by
1H-NMR analysis cIsolated yield dDiastereomeric ratio determined
1
e
1
by H-NMR analysis Conversion judged by H-NMR analysis
fPerformed with NHC filtered from KCl gNR=No reaction
Initially the scope of the reaction was examined using
a range of α,β-unsaturated acyl fluorides 3 (Table 2). In
all cases good yields of electron rich (1e and f) and elec-
tron poor (1g and h) cyclopentanes were obtained, with
the products isolated as a single diastereoisomer (dr
>20:1). Heteroaromatics were tolerated (furanyl 1i),
while aliphatic acyl fluoride 3j gave the expected cyclo-
pentane 1j, although in modest yield. Variation in the
cyclopropyl partner was examined next. As discussed,
the electronics of the ester play a significant role in the
reaction outcome, with more electron rich aromatics
generally providing higher yields. Additionally, when
dimethyl substituents replaced the cyclohexyl the yield of
1l was a disappointing 47% (cf. 93% with cyclohexyl, 1f).
However, changing the ester to the more electron rich
o,p-(CH3O)2C6H3 provided dimethyl cyclopentane 1m in
an acceptable 79% yield. Use of this electron rich ester
was often beneficial, with cyclopenytl products 1n and o,
and cycloheptyl 1p and q, formed in good yields.
10 mol% A1•HCl,
O
O
F
Ph
Ph
10 mol% LiHMDS,
THF, 4Å sieves
#78 ºC$rt, 14h
OAr
TMSO
O
OAr
O
(4)
Ar = p-CH3OC6H4
O
(±)-1d,
36% yield
3a
(±)-2d
1.001(1)
O
0.978(1)
10 mol% A1,
5 equiv. (1:1)
3a and D-3a,
THF, 4Å sieves
#78 ºC$rt, 14h
H/D
O
H/D
F
Ph
Ph
H/D
OAr
OAr
3
2
TMSO
H/D
O
O
(5)
Ar = p-CH3OC6H4
!-D-3a
or
"-D-3a
O (±)-3D-1d
or
(±)-2D-1d
(±)-2d
O
O
F
Ph
TMSO
Ph
Ph
O
10 mol% A2,
THF, 4Å sieves
#78 ºC$rt, 14h
OAr
OAr
(6)
O
OAr O
O
3a
Ar = p-CH3OC6H4
iPr
O
O
(±)-2d
(±)-1d
(±)-1d%
N
O
To clarify the mechanism of the reaction (Scheme 1)
salt effects were examined. The role of the counter ion in
the anionic oxy-Cope rearrangement is well document-
ed,16 with lithium providing negligible rate acceleration
compared to potassium. Thus generation of the NHC
using LiHMDS rather than KHMDS was examined,
62% yield
1d:d% 1:1
Ph
Slowed
aldol cf. A1
N
iPr
OAr
O
O
Scheme 1. Mechanistic studies.
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Journal of the American Chemical Society
over limiting step, hence this approach should be appro- A highly rapid Claisen rearrangement under condi-
1
2
3
4
5
6
7
8
priate.17 While no SKIE was observed at the α-position a
modest inverse SKIE was observed at the β-position,
supportive of turn over limiting Claisen rearrangement.6
Finally the reaction shows a marked sensitivity to the
bulk of the catalyst, with A2 eroding the diastereoselec-
tivity (eq. 6). This relates not to the Claisen step, but ra-
ther the aldol/lactonization which is presumably slowed
by the bulk of the catalyst, allowing rotation of enolate
III and hence formation of 1d and 1d'.
tions of NHC catalysis has been achieved with substrates
bearing C2 and C4 oxygenation. This has allowed the
NHC catalyzed (3 + 2) annulation to be achieved with-
out competing side reactions involving either acyl anion
or enolate chemistry. The realization of this transfor-
mation represents a new catalytic Claisen rearrangement
of synthetic utility. In addition this reaction should serve
to inform, and enable, future studies in NHC acyl azoli-
um catalysis.
9
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13
14
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60
Taken together, we postulate that addition of IMes
(A1) to acyl fluoride 3a results in formation of acyl az-
olium II and, following desilylation and retro-aldol reac-
tion of 2d, enolate VI. Hemiacetal formation, and subse-
quent turnover limiting Ireland-Coates Claisen rear-
rangement, then provides V which undergoes aldol cy-
clization and lactonization to afford cyclopentane 1 and
regenerate the catalyst (Scheme 2).
ASSOCIATED CONTENT
1
Supporting Information. Characterization data, H, and
13C-NMR spectra, and detailed experimental procedures are
available free of charge via the Internet at
http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Author
O
O
Ph
ArO
david.lupton@monash.edu
F
Ph
OAr
O
Funding Sources
O
OTMS
Mes
O
3a
2d
No competing financial interests have been declared.
N
TMSF
1d
N
Mes
ACKNOWLEDGMENT
Mes
O
Ph
OAr
A1
N
We acknowledge the support of James (Zhen) Wang for
instrumental analysis, financial support from the ARC
through the Discovery and Future Fellowship programs and
Monash University through the Research Accelerator Pro-
gram. We thank Professor Tomislav Rovis (Colorado State
University) for donation of the imidazolium precursor to
B2.
O
N
Mes
N
Mes
OAr
O
O
Ph
II
O
N
VII
VI
Mes
O
Mes
Mes
Ph
Ph
N
N
O
O
N
N
O
O
REFERENCES
OAr
O
OAr
IV
Mes
Mes
O
1
V
For reviews on the Claisen rearrangement see: (a) Castro, A. M. M.
Chem. Rev. 2004, 104, 2939 for seminal contributions on catalytic
enantioselective rearrangements see: (b) Abraham, L.; Czerwonka, R.;
Hiersemann, M. Angew. Chem. Int. Ed. 2001, 40, 4700 (c) Uyeda, C.;
Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130, 9228.
Scheme 2. Postulated mechanism
To probe the significance of C2-oxygenation the annu-
lation of 3a with 5 was examined (Scheme 3). Unfortu-
nately rather than providing cyclopentane 6 lactol ester 7
formed in 97% yield. Presumably this failure is due to the
slower Claisen rearrangement, thereby allowing compet-
ing O-acylation of the lactolate derived from VIII. This
result highlights challenges developing cascades with less
facile NHC catalyzed rearrangements.
2 For an informative introduction to this field see Mahatthananchai, J.;
Kaeobamrung, J.; Bode, J. W. ACS Catal. 2012, 2, 494.
3
Coates, R. M.; Rogers, B. D.; Hobbs, S. J.; Peck, D. R.; Curran, D.
P. J. Am. Chem. Soc. 1987, 109, 1160.
4 For mechanistic studies see: (a) Mahatthanachai, J.; Zheng, P.; Bode,
J. W. Angew. Chem. Int. Ed. 2011, 50, 1673 (b) Candish, L.; Lupton,
D. W. Org. Biomol. Chem. 2011, 9, 8182 (c) Lyngvi, E.; Bode, J. W.;
Schoenebeck, F. Chem. Sci. 2012, 3, 2346 (d) Samanta, R. C.; Maji,
B.; De Sarkar, S.; Bergander, K.; Froehlich, R.; Mueck-Lichtenfeld,
C.; Mayr, H.; Studer, A. Angew. Chem Int. Ed. 2012, 51, 5234.
O
5
Ph
O
For Michael or Claisen reactions of α,β-unsaturated acyl azoliums
Mes
(a) Ryan, S. J.; Candish, L.; Lupton, D. W. J. Am Chem. Soc. 2009,
131, 14176 (b) Kaeobamrung, J.; Mahatthananchai, J.; Zheng, P.;
Bode, J. W. J. Am. Chem. Soc. 2010, 132, 8810 (c) De Sarkar, S.;
Studer, A. Angew. Chem. Int. Ed. 2010, 49, 9266 (d) Candish, L.;
Lupton, D. W. Org. Lett. 2010, 12, 4836 (e) Zhu, Z.-Q.; Xiao, J.-C.
Adv. Synth. Catal. 2010, 49, 9266 (f) Rong, Z.-Q.; Jia, M.-Q.; You,
S.-L. Org. Lett. 2011, 13, 4080 (g) Zhu, Z.-Q.; Zheng, X.-L.; Jiang,
N.-F.; Wan, X.; Ziao, J.-C. Chem. Commun. 2011, 47, 8670 (h)
Biswas, A.; De Sarkar, S.; Froehlich, R.; Studer, A. Org. Lett. 2011,
13, 4966 (i) Wanner, B.; Mahatthananchai, J.; Bode, J. W. Org. Lett.
2011, 13, 5378 (j) Candish, L.; Lupton, D. W. Chem. Sci. 2012, 3,
N
Ph
O
F
Ph
N
O
O
O
Ph
O
Mes
O
II
Ph
Ph
10 mol% A1,
THF, 4Å sieves
3a
(±)-6
TMSO
Ph
O
O
!78 °C"rt, 14h
O
(±)-5
Ph
VIII
(±)-7,
97% yield
Scheme 3. Attempted (3 + 2) annulation of 3a and 5.
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Journal of the American Chemical Society
Page 4 of 5
17 For details on determination of α- and β-SKIEs using internal com-
380 (k) Sun, F.-G.; Sun, L.-H.; Ye, S. Adv. Synth. Catal. 2011, 353,
3134 (l) Yao, C.; Wang, D.; Lu, J.; Li, T.; Jiao, W.; Yu, C. Chem.
Eur. J. 2012, 18, 1914 (m) Du, D.; Hu, Z.; Jin, J.; Lu, Y.; Tang, W.;
Wang, B.; Lu, T. Org. Lett. 2012, 14, 1274 (n) Kravina, A. G.; Ma-
hatthananchai, Bode, J. W. Angew. Chem. Int. Ed. 2012, 51, 9433 (o)
Romanov-Michailidis, F.; Besnard, C.; Alexakis, A. Org. Lett. 2012,
14, 4906 (p) Biswas, A.; De Sarkar, S.; Tebben, L.; Studer, A. Chem.
Commun. 2012, 48, 5190. For the chemistry of α,β-unsaturated acyl
azoliums in a biological context see: (q) Merski, M.; Townsend, C. A.
J. Am. Chem. Soc. 2007, 129, 15750
pletion studies see: (a) Ryan, S. J.; Stasch, A.; Paddon-Row, M.;
Lupton, D. W. J. Org. Chem. 2012, 77, 8831 and references therein.
For comments regarding when such studies are suitable in the context
of C-H activation see: (b) Simmons, E. M.; Hartwig, J. F. Angew.
Chem. Int. Ed. 2012, 51, 3066
1
2
3
4
5
6
7
8
6
For initial studies on ester enolate Claisen see: (a) Ireland, R. E.;
9
Mueller, R. H. J. Am. Chem. Soc. 1972, 94, 5897 For initial reports on
the Coates-Claisen: (b) Coates, R. M.; Shah, S. K.; Mason, R. W. J.
Am. Chem. Soc. 1982, 104, 2198 for computation studies into the
effect of alkoxide introduction see: (c) Yoo, H. Y.; Houk, K. N. J.
Am. Chem. Soc. 1997, 119, 2877.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
7 For a recent review on Cascade/Domino NHC catalysis see Gross-
mann, A.; Enders, D. Angew. Chem. Int. Ed. 2012, 51, 314.
8
For selected NHC catalyzed reactions culminating in β-
lactonization, see: (a) Burstein, C.; Tschan, S.; Xie, X.; Glorius, F. Syn-
thesis 2006, 2418 (b) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J.
Am. Chem. Soc. 2006, 128, 8736 (c) Chiang, P.-C.; Kaeobamrung, J.;
Bode, J. W. J. Am. Chem. Soc. 2007, 129, 3520 (d) Wadamoto, M.;
Phillips, E. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2007,
129, 10098 (e) He, M.; Bode, J. W. J. Am. Chem. Soc. 2008, 130, 418 (f)
Kaeobamrung, J.; Bode, J. W. Org. Lett. 2009, 11, 677 (g) Phillips, E.
M.; Roberts, J. M.; Scheidt, K. A. Org. Lett. 2010, 12, 2830 (h) Cohen,
D. T.; Eichman, C. C.; Phillips, E. M.; Zarefsky, E. R.; Scheidt, K. A.
Angew. Chem. Int. Ed. 2012, 51, 7309
9 For a review on the chemistry of donor-acceptor cyclopropanes see:
(a) Reissig H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151 for ring
opening using fluoride see: (b) Kunkel, E.; Reichelt, I.; Reissig, H.-U.
Liebigs Ann. Chem. 1984, 802 for a review of Wenkert’s contribu-
tions to the chemistry of donor acceptor cycloproanes see: (c)
Wenkert, E. Acc. Chem. Res. 1980, 13, 27
10
For other NHC catalyzed reactions exploiting ring opening of cy-
clopropanes see: (a) Sohn, S. S.; Bode, J. W. Angew. Chem. Int. Ed.
2006, 45, 6021 (b) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007,
129, 13798 (c) Li, G.-Q.; Dai, L.-X.; You, S.-L. Org. Lett. 2009, 11,
1623 (d) Li, L.; Du, D.; Ren, J.; Wang, Z. Eur. J. Org. Chem. 2011,
614
11
The role of salts in NHC organocatalysis has been documented
previously by ourselves and others. For cooperative catalysis using
Lewis acids and nucleophilic carbenes see: Cohen, D. T.; Scheidt, K.
A. Chem. Sci. 2012, 3, 53 and references therein
12
See for example: Ryan, S. J.; Candish, L.; Lupton, D. W. J. Am.
Chem. Soc. 2011, 133, 4694.
13
nOe analysis of was used to determine relative stereochemistry, see
for example 1f.
H3CO
O
H
Op-OCH3C6H4
R
H
nOe
H
H
O
O
R
nOe
1f, R = -(CH2)5-
14
Struble, J. R.; Kaeobamrung, J.; Bode, J. W. Org. Lett. 2008, 10,
957
15 Acyl azolium reactions using acyl fluorides are sensitive to the type
of NHC used. For reviews on the properties of NHCs see: (a) Dröge,
T.; Glorius, F. Angew. Chem. Int. Ed. 2010, 49, 6940 (b) Maji, B.;
Breugst, M.; Mayr, H. Angew. Chem. Int. Ed. 2011, 50, 6915. For
discussions on the impact of the azolium type on the benzoin conden-
sation see: (c) Holloczki, O.; Kelemen, Z.; Nyulaszi, L. J. Org. Chem.
2012, 77, 6014. For discussion of the role of the electronics of the N-
aryl group in triazolium based NHC-catalysis see: (d) Rovis, T. Chem.
Lett. 2008, 37, 2 (e) Mahatthananchai, J.; Bode, J. W. Chem. Sci.
2011, 3, 192.
16
The role of counter ion in the anionic Cope is documented in Ev-
ans’ seminal communication: Evans, D. A.; Golub, A. M. J. Am.
Chem. Soc. 1975, 97, 4765.
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Page 5 of 5
Journal of the American Chemical Society
Graphical Abstract
1
2
O
F
Ph
3
4
5
6
7
8
Ph
10 mol% IMes,
THF, 4Å sieves,
-78 ºC!rt,14h
O
OAr
O
CO2Ar
CH3
TMSO
Ar = o,p-(CH3O)2C6H3
O
CH3
H3C
H3C
and 16 other examples
41–93% yield
dr>20:1
Mes
Ph
N
CH3
9
O
Ireland-Coates
Claisen rearrangement
N
CH3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
OAr
Mes
O
5
ACS Paragon Plus Environment