Organocatalysis of the Morita-Baylis-Hillman alkylation using trialkylphosphines

Article abstract of DOI:10.1055/s-2006-951531

Using a catalytic amount of trialkylphosphines, alkyl halides undergo efficient intramolecular Morita-Baylis-Hillman cyclization. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-951531

3334
LETTER
Organocatalysis of the Morita–Baylis–Hillman Alkylation Using
Trialkylphosphines
O
rganocatalysis of the
a
Morita–Ba
r
ylis–Hill
i
ma
n
A
e
lkylation Using
T
E
rialkylphosphin
.
es Krafft,* Kimberly A. Seibert
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA
Fax +1(850)6447409; E-mail: mek@chem.fsu.edu
Received 27 June 2006
sure of enone 1 (1 mmol) in tert-butanol–dichloromethane
(2 mL, 1:1) and a 0.2 M solution of potassium hydroxide
(5 mL), to BnEt3NCl (27 mg, 0.1 mmol) and a stoichio-
metric amount of tributylphosphine, the desired product,
enone 2, was obtained with no reduction in yield when
compared to the stoichiometric reaction involving the
sequential addition of reagents.10a This result suggested
that all the reagents required for the stepwise process are
compatible with each other.
Abstract: Using a catalytic amount of trialkylphosphines, alkyl ha-
lides undergo efficient intramolecular Morita–Baylis–Hillman cy-
clization.
Key words: alkylation, cyclization, cycloalkenone, organocataly-
sis, ring closure
Organocatalysis, an acceleration of chemical reactions us-
ing a substoichiometric quantity of an organic compound,
is an important tool for making carbon–carbon bonds, and
possibly one of the most fundamental and important pro-
cesses for the construction of organic molecular frame-
works.1 Organocatalyzed reactions have broad
applications and have been used extensively in the Man-
nich, Wittig,2 Aldol3 and Michael4 reactions and have
more recently been applied to the Stetter,5 Sonagashira,6
Ullmann,7 and aza-Henry reactions.8 In the past few years
there has been significant progress in realizing more ef-
fective catalysis of the organocatalyzed Morita–Baylis–
Hillman (MBH) reaction. While the MBH reaction has
drawn increasing attention in the past 15 years and has
seen tremendous refinement of conditions, trialkyl-
phosphines9 as catalysts have not been as widely em-
ployed as tertiary amines. Furthermore, while the
intermolecular MBH reaction has been studied extensive-
ly, intramolecular cycloadditions, which are of particular
importance in that they allow for construction of function-
alized ring systems starting from simple acyclic starting
materials, have not been as thoroughly investigated. Re-
cently, we reported an intramolecular MBH reaction using
saturated alkyl halides as the electrophilic partner mediat-
ed by stoichiometric amounts of a trialkylphosphine.10
Having provided the first examples of the Morita–Baylis–
Hillman reaction employing an sp3- hybridized electro-
phile, we set out to augment the synthetic utility and in-
crease the efficiency of the reaction by employing
catalytic amounts of the nucleophilic organomediator.
With this result, it appeared that use of a catalytic amount
of trialkylphosphine should be feasible. Accordingly,
enone 1, in a solution of 0.5 M tert-butanol–dichloro-
methane (1:1), 0.2 M aqueous potassium hydroxide (1
equiv), and BnEt3NCl (0.1 equiv), was treated with 20
mol% of trimethylphosphine. However, only starting
material was recovered suggesting that the volatility of tri-
methylphosphine may be a problem. Elimination of the
assumed problem by use of tributylphosphine allowed the
desired product to be obtained in an 84% yield (Table 1,
entry 2). Building on this initial result we set out to further
optimize the reaction conditions and investigate the role
of the components involved in the reaction. In the absence
of dichloromethane the reaction was very slow and after
five days had not gone to completion, producing only 56%
of the desired product (Table 1, entry 3). The reaction was
also run using various amounts of tributylphosphine in or-
der to determine the optimal percent loading of the cata-
lyst. Upon treatment of enone 1 with 10 mol% of
tributylphosphine under the standard conditions a reduced
Table 1 Trialkylphosphine-Mediated Intramolecular Cycloaddition
of Bromo Enone 1
O
O
x mol% PR3, KOH
Br
BnEt3NCl, H2O
organic phase
1
2
We disclose herein a catalytic version of the intramole-
cular cycloalkylation using saturated alkyl halides as the
electrophilic partner. To assess the feasibility of the
proposed transformation and the compatibility of the
reagents, trialkylphosphine-mediated intramolecular cy-
cloaddition of bromo enone 1 was attempted. Upon expo-
Entry
PR3
x mol%
Organic phase
Yield (%)
1
2
3
4
5
PMe3
PBu3
PBu3
PBu3
–
20
20
20
10
–
CH2Cl2–t-BuOH
CH2Cl2–t-BuOH
t-BuOH
0
84
56
65
95a
CH2Cl2–t-BuOH
CH2Cl2–t-BuOH
SYNLETT 2006, No. 19, pp 3334–3336
0
1
.1
2
.2
0
0
6
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-951531; Art ID: S13806ST
© Georg Thieme Verlag Stuttgart · New York
a Recovered starting material.

LETTER
Organocatalysis of the Morita–Baylis–Hillman Alkylation Using Trialkylphosphines
3335
yield of 65% of the desired product was obtained in com- strated the necessity of the dichloromethane and investi-
parison to the 84% yield when 20 mol% of the catalyst gated the role of the base, we focused our attention on the
was used (Table 1, entry 2 vs. entry 4). With these results concentration of the organic phase as a possible avenue to
in hand it was necessary to discount the possibility of improve the reaction and obtain the desired products.
base-catalyzed enolate formation followed by alkylation With this in mind, treatment of phenyl enone 6 with 20
as a means of forming cyclic enone, 2. Reaction of bro- mol% of tributylphosphine, potassium hydroxide and
mide 1 with aqueous potassium hydroxide and BnEt3NCl BnEt3NCl while employing an increased concentration of
in 0.5 M tert-butanol–dichloromethane (1:1) in the ab- the organic phase to 5 M, 33% of product 16 was recov-
sence of trialkylphosphine gave 95% yield of starting ma- ered. The concentration was subsequently decreased to
terial suggesting the reaction was not simply base- 3 M and eventually 1 M, which yielded 45% of the desired
catalyzed but required the use of an organocatalyst product (Table 2, entry 4). Further dilution decreased the
(Table 1, entry 5). With these optimized reaction condi- yield to where little or no product was formed. Having
tions, application to a more diverse set of substrates was established a newly optimized procedure for formation of
performed (Table 2).
six-membered rings, bromides 3 and 7 were submitted to
the new conditions giving 43% and 94% of the desired
products, respectively (Table 2, entries 1 and 5).
Five-membered rings were readily formed in yields equal
to those reported using stoichiometric amounts of tri-
alkylphosphine.10 Unfortunately, upon increasing the In conclusion, we have demonstrated catalysis of the first
anticipated ring size by one carbon, difficulties were Morita–Baylis–Hillman cycloalkylation using sp3-hybrid-
encountered in the cyclization under the previously opti- ized alkyl halides as the electrophilic partner. Five- and
mized conditions with a couple of exceptions. Highly ac- six-membered rings were formed efficiently with little to
tivated, electron-deficient enone 8 and phenyl enone 4 no loss in yield upon comparison to yields obtained when
readily cyclized with the latter owing to the ease of cy- stoichiometric amounts of trialkylphosphines were em-
clization to Thorpe–Ingold assistance provided by substi- ployed. Future studies will be devoted to the development
tution on the tether. However without the substitution on of related transformations, including variations of the
the tether, phenyl enone 6 failed to cyclize in spite of the enone moiety in addition to application of this method to
stability of the enolate formed upon conjugate addition of the formation of multicyclic ring systems.
the phosphine nucleophile. With these results in hand, fur-
ther optimization was needed in order to effect cyclization
of the less activated enones that form six-membered rings.
Acknowledgment
The National Science Foundation and the MDS Research Founda-
tion supported this work.
Having optimized the percent loading of catalyst, demon-
Table 2 Catalytic MBH Cycloalkylation Reactions11,12
O
O
R
PBu3, KOH
BnEt3NCl, H2O
Br
R
0.5 M in CH2Cl2–t-BuOH (1:1)
n
n
Entry
Bromide
Enone
Time (h)
Yield (%)
20% PBu3 100% PBu3
1
2
3
4
R = Me
R = Ph
E = CO2Et
13
14
O
5
2
43
91
99
90
O
R
Br
Br
R
E
E
E
E
3
4
5
6
5
6
7
8
R = Me
R = Ph
R = naphth
R = p-NO2C6H4
15
16
17
18
–
5
5
0
45
94
97
80 (PMe3)
100
O
R
O
O
R
R
95
0.1
99 (PMe3)
7
8
9
1
9
10
11
R = Me
R = Ph
R = naphth
R = p-NO2C6H4
2
19
20
21
3
3
2
84
88
97
99
79
87
O
R
Br
96 (PMe3)
97
10
0.1
11
12
22
5
90
90
O
H
H
O
H
H
CH3
CH3
Br
Synlett 2006, No. 19, 3334–3336 © Thieme Stuttgart · New York

3336
M. E. Krafft, K. A. Seibert
LETTER
3106, 2937, 2861, 1673, 1620, 1601, 1523, 1344 cm–1. Anal.
Calcd for C13H14O3NBr: C, 50.02; H, 4.52. Found: C, 50.05;
H, 4.67.
References and Notes
(1) (a) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 43,
5138. (b) Saeyad, J.; List, B. Org. Biomol. Chem. 2005, 3,
719. (c) Asymmetric Organocatalysis; Berkessel, A.;
Gröger, H., Eds.; Wiley-VCH: Weinheim, 2005.
(d) Ramachary, D. B.; Barbas, C. F. Chem. Eur. J. 2004, 10,
5323. (e) List, B. Tetrahedron 2002, 58, 5573.
(2) Maryanoff, B. E.; Rietz, A. B. Chem. Rev. 1989, 89, 863.
(3) (a) Alcaide, B.; Almendros, P. Eur. J. Org. Chem. 2002,
1595. (b) Saito, S.; Yamamoto, H. Acc. Chem. Res. 2004, 37,
570. (c) Palomo, C.; Oiarbide, M.; Garcia, J. M. Chem. Soc.
Rev. 2004, 33, 65.
(4) (a) Brown, S. P.; Goodwin, N. C.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2003, 125, 1192. (b) Paras, N. A.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124, 7894.
(c) Berner, O. M.; Tedeshi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 1877.
(5) (a) Kerr, M. S.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc.
2002, 124, 10298. (b) Kerr, M. S.; Rovis, T. J. Am. Chem.
Soc. 2004, 126, 8876.
(6) (a) Appukkuttan, P.; Dehain, W.; Van der Eycken, E. Eur. J.
Org. Chem. 2003, 4713. (b) Leadbeater, N. E.; Marco, M.;
Tominack, B. J. Org. Lett. 2003, 5, 3919.
(7) Ma, D.; Cai, Q. Synthesis 2004, 128.
(8) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org.
Lett. 2004, 6, 625.
(9) Roush, W. R.; Methot, J. L. Adv. Synth. Catal. 2004, 346,
1035.
(10) (a) Krafft, M. E.; Seibert, K. A.; Haxell, T. F. N. Chem.
Commun. 2005, 5772. (b) Krafft, M. E.; Haxell, T. F. N.;
Seibert, K. A.; Abboud, K. A. J. Am. Chem. Soc. 2006, 128,
4174.
Bromide 10: 1H NMR (500 MHz, CDCl3): d = 8.45 (m, 1 H,
aromatic), 8.03 (m, 1 H, aromatic), 7.98 (m, 1 H, aromatic),
7.90 (m, 2 H, aromatic), 7.58 (m, 2 H, aromatic), 7.14 (d,
J = 15.38 Hz, 1 H, CH=CHCH2), 7.07 (td, J = 6.6, 15.4 Hz,
1 H, CH=CHCH2), 3.49 (t, J = 6.6 Hz, 2 H, BrCH2CH2), 2.56
(dt, J = 6.6, 7.3 Hz, 2 H, CH=CHCH2), 2.13 (tt, J = 6.6, 7.3
Hz, 2 H, CH2CH2Br). 13C NMR (75 MHz, CDCl3): d =
189.8, 146.8, 135.2, 134.8, 132.3, 129.8, 129.3, 128.3,
128.2, 127.6, 126.6, 126.5, 124.2, 32.7, 30.9, 30.7. FTIR
(neat): 3055, 2930, 1665, 1617, 1291 cm–1. Anal. Calcd for
C16H15OBr: C, 63.38; H, 4.99. Found: C, 63.39; H, 4.93.
Enone 11: 1H NMR (500 MHz, CDCl3): d = 8.32 (m, 2 H,
aromatic), 8.05 (m, 2 H, aromatic), 7.08 (td, J = 7.1, 15.4 Hz,
1 H, CH=CHCH2), 6.93 (td, J = 1.5, 15.4 Hz, 1 H,
CH=CHCH2), 3.46 (t, J = 7.0 Hz, 2 H, CH2Br), 2.55 (dtd,
J = 1.5, 7.0, 7.1 Hz, 2 H, CH=CHCH2), 2.11 (tt, J = 7.0, 7.0
Hz, 2 H, CH2CH2Br). 13C NMR (75 MHz, CDCl3): d =
188.8, 149.9, 149.4, 142.4, 129.3, 126.3, 123.7, 35.5, 31.0,
30.6. FTIR (neat): 2936, 2854, 1674, 1622, 1602, 1436,
1248, 1028 cm–1. Anal. Calcd for C12H12O3NBr: C, 48.34; H,
4.06; N, 4.70. Found: C, 48.67; H, 4.34; N, 4.75.
Enone 17: 1H NMR (500 MHz, CDCl3): d = 8.12 (m, 1 H,
aromatic), 7.92 (m, 1 H, aromatic), 7.87 (m, 2 H, aromatic),
7.75 (m, 1 H, aromatic), 7.55 (m, 2 H, aromatic), 6.64 (tt,
J = 2.0, 7.3 Hz, 1 H, C=CHCH2), 2.49 (dtt, J = 2.0, 2.4, 6.1
Hz, 2 H, CH=CHCH2), 2.30 (ttd, J = 2.4, 6.1, 7.2 Hz, 2 H,
CH2CH=C), 1.78 (tt, J = 6.1, 6.1 Hz, 2 H, C=CH2CH2), 1.71
(tt, J = 6.1, 6.1 Hz, 2 H, C=CHCH2CH2). FTIR (neat): 2918,
2849, 1638, 1465, 1282 cm–1. Anal. Calcd for C17H16O: C,
86.40; H, 6.82. Found: C, 86.10; H, 6.43.
Enone 18: 1H NMR (500 MHz, CDCl3): d = 8.27 (m, 2 H,
aromatic), 7.73 (m, 2 H, aromatic), 6.57 (tt, J = 2.0, 7.4 Hz,
1 H, C=CHCH2), 2.43 (dtt, J = 2.0, 2.4, 6.2 Hz, 2 H,
CH=CCH2), 2.30 (ttd, J = 2.4, 6.2, 7.6 Hz, 2 H, C=CHCH2),
1.75 (tt, J = 6.2, 6.2 Hz, 2 H, C=CHCH2CH2), 1.69 (tt, J =
6.2, 6.2 Hz, 2 H, C=CHCH2CH2CH2). 13C NMR (75 MHz,
CDCl3): d = 195.9, 149.0, 146.5, 144.4, 138.6, 129.6, 123.2,
26.2, 23.4, 21.7, 21.4. HRMS (EI+): m/z calcd for
C13H13O3N: 231.08948; found: 231.08955. FTIR (neat):
2933, 1648, 1301, 1522, 1350 cm–1. Anal. Calcd for
C13H13O3N: C, 67.52; H, 5.67. Found: C, 67.30; H, 5.74.
Enone 20: 1H NMR (500 MHz, CDCl3): d = 8.25 (m, 1 H,
aromatic), 7.83–7.94 (m, 4 H, aromatic), 7.52–7.59 (m, 2 H,
aromatic), 6.61 (tt, J = 1.7, 2.5 Hz, 1 H, C=CHCH2), 2.81
(dtt, J = 1.7, 2.2, 7.5 Hz, 2 H, CH=CCH2), 2.67 (tdt, J = 2.2,
2.5, 7.5 Hz, 2 H, CH2CH=C), 2.06 (tt, J = 7.5, 7.5 Hz, 2 H,
CH2CH2CH=C). 13C NMR (75 MHz, CDCl3): d = 194.1,
146.7, 144.6, 136.1, 134.9, 132.2, 129.9, 129.1, 128.0,
127.8, 127.7, 126.5, 125.1, 34.3, 32.0, 22.7. HRMS (FAB+):
m/z [M + Na] calcd for C16H14ONa: 245.0948; found:
245.0942. FTIR (neat): 2952, 1636, 1355, 1299 cm–1. Anal.
Calcd for C16H14O: C, 86.45; H, 6.35. Found: C, 86.41; H,
6.33.
(11) General Procedure: To the halide in a 0.5 M solution of t-
BuOH–CH2Cl2 (1:1), were added a 0.2 M KOH solution (1
equiv) and BnEt3NCl (10 mol%). The reaction mixture was
then treated with tributylphosphine (20 mol%) and allowed
to stir at ambient temperature until the reaction was complete
(TLC analysis). For entries 1, 4 and 5 (Table 2), a 1.0 M
solution of t-BuOH–CH2Cl2 (1:1) was employed for the
catalytic reaction.
(12) For characterization data of compounds 1–6, 9, 12–16, 19,
and 22, see ref. 10a.
Bromide 7: 1H NMR (500 MHz, CDCl3): d = 8.45 (m, 1 H,
aromatic), 8.02 (m, 1 H, aromatic), 7.98 (m, 1 H, aromatic),
7.90 (m, 2 H, aromatic), 7.56 (m, 2 H, aromatic), 7.12 (td,
J = 6.0, 15.45 Hz, 1 H, CH=CHCH2), 7.07 (d, J = 15.45 Hz,
1 H, CH=CHCH2), 3.46 (t, J = 6.6 Hz, 2 H, BrCH2CH2), 2.41
(dt, J = 6.0, 7.3 Hz, 2 H, CH=CHCH2), 1.97 (tt, J = 6.6, 7.5
Hz, 2 H, CH2CH2Br), 1.74 (tt, J = 7.3, 7.5 Hz, 2 H, CH=CH
CH2CH2). 13C NMR (75 MHz, CDCl3): d = 190.3, 148.5,
135.3, 135.1, 132.4, 129.9, 129.4, 128.4, 128.3, 127.7,
126.7, 126.2, 124.4, 32.3, 32.1, 31.8, 26.6. HRMS (FAB+):
m/z [M + Na] calcd for C17H17OBrNa: 339.0368; found:
339.0360. FTIR (neat): 2934, 1691, 1665, 1615, 1460, 1295
cm–1. Anal. Calcd for C17H17OBr: C, 64.37; H, 5.40. Found:
C, 64.44; H, 5.46.
Enone 21: 1H NMR (500 MHz, CDCl3): d = 8.28 (m, 2 H,
aromatic), 7.84 (m, 2 H, aromatic), 6.57 (tt, J = 2.0, 12.4 Hz,
1 H, C=CHCH2), 2.76 (dtt, J = 2.4, 7.6, 12.4 Hz, 2 H,
CH=CCH2), 2.66 (tdt, J = 2.0, 2.4, 7.6 Hz, 2 H, C=CHCH2),
2.04 (tt, J = 7.6, 7.6 Hz, 2 H, C=CHCH2CH2). 13C NMR (75
MHz, CDCl3): d = 192.0, 149.5, 149.1, 144.5, 144.3, 129.5,
123.4, 34.6, 31.5, 22.7. HRMS (EI+): m/z [M + Na] calcd for
C12H11O3N: 217.07378; found: 217.07390. FTIR (neat):
2957, 2871, 1646, 1601, 1522, 1348 cm–1. Anal. Calcd for
C12H11O3N: C, 66.35; H, 5.10. Found: C, 66.21; H, 5.10.
Bromide 8: 1H NMR (500 MHz, CDCl3): d = 8.32 (m, 2 H,
aromatic), 8.05 (m, 2 H, aromatic), 7.10 (td, J = 6.8, 15.4 Hz,
1 H, CH=CHCH2), 6.89 (td, J = 1.5, 15.4 Hz, 1 H,
CH=CCH2), 3.44 (t, J = 6.6 Hz, 2 H, CH2Br), 2.40 (ddt, J =
1.5, 6.6, 7.2 Hz, 2 H, C=CHCH2), 1.94 (tt, J = 6.6, 7.2 Hz, 2
H, CH2CH2Br), 1.73 (tt, J = 7.2, 7.2 Hz, 2 H,
C=CHCH2CH2). 13C NMR (75 MHz, CDCl3): d = 188.8,
150.8, 149.7, 142.4, 129.4, 129.2, 125.6, 123.6, 123.5, 33.1,
31.9, 31.7, 26.3. HRMS (FAB+): m/z [M + H+] calcd for
C13H15O3NBr: 312.0237; found: 312.0235. FTIR (neat):
Synlett 2006, No. 19, 3334–3336 © Thieme Stuttgart · New York