Design and synthesis of (E)-1-((3-ethyl-2,4,4-trimethylcyclohex-2- enylidene)methyl-4-substituted benzenes from 1-(2,6,6-trimethylcyclohex-1-enyl) ethanol

Article abstract of DOI:10.1039/b823063c

A novel strategy for synthesizing (E)-1-((3-ethyl-2,4,4-trimethylcyclohex- 2-enylidene)methyl-4-substituted benzenes from 1-(2,6,6-trimethylcyclohex-1- enyl)ethanol 3 has been developed; the allylic alcohol 3 was treated with PPh₃·HBr in methan

Full text of DOI:10.1039/b823063c

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Design and synthesis of (E)-1-((3-ethyl-2,4,4-trimethylcyclohex-2-
enylidene)methyl-4-substituted benzenes from
1-(2,6,6-trimethylcyclohex-1-enyl)ethanolw
Bhaskar C. Das,*ab Sakkarapalayam M. Mahalingam,a Todd Evans,*ac George W. Kabalka,d
J. Anguianoa and K. Hemaa
Received (in College Park, MD, USA) 22nd December 2008, Accepted 12th February 2009
First published as an Advance Article on the web 9th March 2009
DOI: 10.1039/b823063c
A
novel strategy for synthesizing (E)-1-((3-ethyl-2,4,4-
Electrocyclizations of conjugated trienes offer a powerful
ring-forming strategy, with the creation of one or two new
stereocenters.9–12 Realizing the importance of 1,3-dienes and
our novel finding to synthesize 1,3-dienes from allylic alcohol
3, prompted us to explore this result to synthesize 1,3-dienes
and trienes. We wish to report the reaction of unusual
phosphonium ylide 4 with aldehydes in presence of base offers
an efficient, direct route to a number of highly substituted
1,3-dienes. Our original goal was to synthesize compounds
1a–c (Fig. 1) as new retinoic acid analogs by introducing
constraints via a phenyl ring.
trimethylcyclohex-2-enylidene)methyl-4-substituted
from 1-(2,6,6-trimethylcyclohex-1-enyl)ethanol
benzenes
3
has been
developed; the allylic alcohol 3 was treated with PPh3ÁHBr in
methanol followed by aldehydes in the presence of a base and
furnished the 1,3-dienes in moderate to good yields (79–86%).
In the context of an ongoing chemical biology project, studying
the role of retinoic acid signaling pathways during zebrafish
embryogenesis, we synthesized novel retinoid libraries.
Retinoids (retinoic acid analogues) play key roles in embryo-
genesis and for maintenance of various cellular processes
such as cell growth and differentiation.1 Retinoids also have
clinical value for cancer chemoprevention and therapy,
although their use is limited by toxicity and teratogenecity at
pharmacological doses.2 Retinoids exert their biological
effects by activating nuclear receptors and modulating gene
transcription.3 A clear understanding of the biological roles of
the retinoid receptor families would greatly facilitate the
design of retinoid analogues that could be targeted for specific
diseases to improve the therapeutic index.4 A number of
synthetic retinoids have been synthesized that interact
selectively with its receptors.5 Understanding the importance
of the retinoids we were keen to synthesize compounds 1a–c as
new retinoic acid analogs by introducing a constrained phenyl
ring system in the place of conjugated alkene backbone
(spacers). In the process of synthesizing compound 1a, we
encountered an unusual Wittig salt formation from the allylic
alcohol 3 which involved the formation of the unusual 1,3-
diene 2 when the Wittig ylide 4 was treated with aldehyde 5.6
The regio- and stereospecific synthesis of 1,3-dienes is of
great importance in synthetic organic chemistry due to
the frequent occurrence of these fragments in biologically
active natural products, as well as to their utilization in
numerous transformations such as the Diels–Alder reaction.7,8
In the process of synthesizing 1a, from 3, we encountered
the unusual Wittig salt 4 (Scheme 1), which led to the forma-
tion of the unusual 1,3-diene 2 when the ylide 4 was treated
with aldehyde 5.6
The unusual formation of 2 prompted us to explore the
reaction in further detail in an effort to develop a novel
strategy for synthesizing substituted 1,3-dienes and 1,3,5-trienes.
We quickly discovered that the initial reaction conditions were
not optimal for synthesizing 1,3-dienes (Table 1, entry 1).
Using 4-formylbenzoic acid methyl ester 5 as a model
aldehyde, all reaction parameters were reinvestigated. Repre-
sentative examples of solvent, base, reaction time and
temperature studies are listed in Table 1. The solvent and
the base are crucial in achieving high yields. DMF and sodium
Fig. 1
a Department of Developmental & Molecular Biology, Albert Einstein
College of Medicine, Bronx, NY 10461, USA.
E-mail: bdas@aecom.yu.edu; Fax: (+1) 718 430 8853
b Department of Nuclear Medicine, Albert Einstein College of
Medicine, Bronx, NY 10461, USA
c Department of Surgery, Weill Cornell Medical College, New York,
NY 10065, USA. E-mail: tre2003@med.cornell.edu
d Departments of Chemistry and Radiology, University of Knoxville,
Tennessee, TN, USA
w Electronic supplementary information (ESI) available: Complete
experimental procedures and characterization data for all new com-
pounds. See DOI: 10.1039/b823063c
Scheme 1
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 2133–2135 | 2133

View Article Online
Table 1 Optimization of 1,3-diene reaction parameters
Table 2 Synthesis of substituted 1,3-dienes; unusual Wittig reaction
of allylic alcohol 3a
Entry
RCHO
Product
E : Zb
Yieldc (%)
Yield (%)
Entry Solvent Base
T/1C
t/h
6
2
1
2
3
4
5
Et2O
nBuLi
tBuONa (1.1 equiv.) RT
tBuONa (2 equiv.)
RT
tBuONa (2.5 equiv.) RT
tBuONa (3 equiv.)
RT
À78 to RT 30 85
0
1
1 : 0
85
DMF
DMF
DMF
DMF
24 50
20 50
12 20
25
25
65
85
12
0
2
1 : 0.46
80
tert-butoxide at room temperature provided the optimal
conditions for generating 2 in high yield. It is noteworthy that
three equivalents of sodium tert-butoxide leads to the highest
yield of 2 (entry 5) in a one-pot Wittig reaction, followed by
ester hydrolysis.
The structure of 2 was confirmed by NMR (1H, 13C, NOE)
experiments and HRMS. The resonance at d 2.19 (q, 2H) in
the 1H NMR and at d 22.3 in the 13C NMR are characteristic
for the methylene in an ethyl sidechain attached to the
cyclohexene ring. NOE experiments clearly indicate that the
phenyl ring is trans in 2 (1H–1H NOEs, d/ppm: 6.46 - 7.38
(4%), 6.46 - 1.85 (18%), 7.39 - 7.90 (7%), 7.39 - 6.46
(4%), 7.39 - 2.55 (1%), see ESIw).
We next examined the scope of the reaction with a variety
of different aldehydes (Table 2). The reaction proved tolerant
of an electron-withdrawing (p-NO2, entry 2; Table 2)
and -donating (p-F, entry 3; Table 2) on the phenyl ring of
the aldehyde. To prove that our new method can be success-
fully applied to the five-membered ring conjugate, we chose a
furfural as one of the substrates (entry 4; table 2). This gave
the corresponding product with 79% yield. The same trend
was observed with 4-pyridinecarbaldehyde (entry 5; Table 2),
and the reaction gave the corresponding 1,3-diene conjugate
with pyridine moiety in good yield (83%). Besides the
aromatic aldehydes, the a,b-unsaturated aldehydes (entries 6
and 7; Table 2) proved more interesting, and we isolated the
corresponding 1,3,5-trienes in good yields. When ketones were
used as carbonyl compounds (entries 8 and 9, Table 2), no
desired compounds were isolated even at reflux condition for
2 days.
3
4
5
1 : 0.05
78
79
83
1 : 0d
1 : 0d
6
1 : 0d
86
81
7
8
1 : 0d
—
—
—
—
0
0
In an attempt to reduce the number of synthetic steps, we
evaluated the feasibility of a one-pot reaction (Scheme 2).
Gratifyingly, the one-pot conversion of allylic alcohol 3 to the
1,3-diene acid 2 was successful, affording the desired product
in 13 and 52% yields in CH3OH and DMF, respectively. Most
importantly, the direct Wittig reaction of the unusual Wittig
salt with 4-formylbenzoic acid affords 2 in 78% yield
(Scheme 3). This process has potential application in industry
to synthesize products on a gram scale.
9
a
All reactions were performed on 1 mmol of aldehyde with 3 equiv. of
b
tBuONa in DMF for 12 h. The E : Z ratio was determined by 1H
c
NMR. Isolated yield refers to aldehyde. Trace amount of Z isomer
d
1
was observed in H NMR.
A reasonable mechanism for the syntheses of 1,3-dienes and
1,3,5-trienes is presented in Scheme 4. The bromination of
allylic alcohol 3 and addition of PPh3 is envisioned to give the
unusual quaternary Wittig ylide 4, which then converts to a
secondary phosphonium ylide C by treatment with base
t
(nBuLi or BuONa). C then undergoes an intramolecular H+
ꢀc
This journal is The Royal Society of Chemistry 2009
2134 | Chem. Commun., 2009, 2133–2135

View Article Online
protocol for generating valuable building blocks in polyene
syntheses. The variety of substituents in the phenyl ring, the
possible application to five-membered heteroaromatics, and
the extension to conjugated dienes make this method valuable
in the synthesis of small molecules and natural products.
Preliminary attempts to carry out Diels–Alder chemistry using
the 1,3-dienes as well as 6p electrocyclization of the 1,3,5-
trienes and their biological study in zebrafish embryogenesis
are under way.
The author B. C. D. is thankful to AECOM for start-up
funding.
Scheme 2 One-pot Wittig reaction and acid hydrolyis.
Notes and references
1 R. C. Moon, R. G. Mehta, K. V. N. Rao and M. B. Spron, The
Retinoids: Biology, Chemistry and Medicine, ed. A. B. Robert and
D. S. Goodman, Raven Press, New York, 2nd edn, 1994,
pp. 573–630.
2 P. Loeliger, W. Bollag, H. Mayer and K. Europ, J. Med. Chem.,
1980, 15, 9.
3 M. I. Dawson, P. D. Hobbs, K. Derdzinski, R. L.-S. Chan,
J. Gruber, W. Chao, S. Smith, R. W. Thies and L. J. Schiff,
J. Med. Chem., 1984, 27, 1516.
Scheme 3 One-pot Wittig reaction with 4-formylbenzoic acid.
4 J. Mundi, S. R. Frankel, W. H. Miller, Jr, A. Jakubowski,
D. A. Scheinberg, C. W. Young, E. Dmitrovsky and
R. P. Warrell, Jr, Blood, 1992, 79, 299.
5 A. M. Nadzan, Annu. Rep. Med. Chem., 1995, 30, 119.
6 B. C. Das and G. W. Kabalka, Tetrahedron Lett., 2008, 49, 4695.
7 (a) Z. Rappoport, The Chemistry of Dienes and Polyenes, John
Wiley & Sons, Chichester, 1997, vol. 1; (b) Z. Rappoport, The
Chemistry of Dienes and Polyenes, John Wiley & Sons, Chichester,
2001, vol. 2.
8 (a) R. C. Larock, Comprehensive Organic Transformations,
Wiley-VCH, New York, 2nd edn, 1999, ch. 2; (b) A. A. Vasil’ev
and E. P. Sterebryakov, Russ. Chem. Rev., 2001, 70, 735.
9 (a) A. Suzuki, Acc. Chem. Res., 1982, 15, 178; (b) A. Suzuki, Pure
Appl. Chem., 1985, 57, 1749; (c) A. Suzuki, Pure Appl. Chem., 1991,
63, 419; (d) A. Suzuki, Pure Appl. Chem., 1994, 66, 213;
(e) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457;
(f) A. Suzuki, in Metal-Catalyzed Cross-Coupling Reactions, ed.
F. Diederich and P. J. Stang, Wiley-VCH, Weinheim, Germany,
1998, p. 49; (g) N. Miyaura, in Advances in Metal-Organic Chem-
istry, ed. L. S. Liebeskind, JAI Press, London, UK, 1998, vol. 6,
p. 187; (h) A. Suzuki, J. Organomet. Chem., 1999, 576, 147;
(i) T. Jun, T. Kou, Tatsuo and M. Norio, J. Am. Chem. Soc.,
2002, 124, 8001; (j) Z. Xiaoxia and C. L. Richard, Org. Lett., 2003,
5, 2993.
10 (a) F. Fringuelli and A. Taticchi, Dienes in the Diels–Alder
Reaction, Wiley, New York, 1990; (b) W. Carruthers, Cycloaddi-
tion Reactions in Organic Synthesis, Pergamon Press, Oxford, UK,
1990; (c) W. Oppolzer, in Comprehensive Organic Synthesis, ed.
B. M. Trost, Pergamon Press, Oxford, UK, 1991, vol. 5, p. 187;
(d) J. D. Winkler, Chem. Rev., 1996, 96, 167; (e) S. Otto and
J. B. F. N. Engberts, Pure Appl. Chem., 2000, 72, 1365;
(f) A. Kumar, Chem. Rev., 2001, 101, 1.
Scheme 4 Proposed reaction mechanism.
shift to provide D, which subsequently reacts with aldehydes
to furnish dienes E. (see ESIw for other mechanisms).
In support of the postulated mechanism, we isolated one of
the intermediates 4. It is interesting to point out that the
olefinic peaks (d 5.50–5.70) in 1H NMR spectrum of
intermediate 4 (Fig. 3, ESIw) provides evidence that the
triphenylphosphine added to the olefinic double bond of A
via a simple allylic type displacement of bromine. To the best
of our knowledge, this is the first Wittig reaction of this type to
be reported in an allylic alcohol system.
In conclusion, we have developed a general and flexible
approach to highly substituted 1,3-dienes and 1,3,5-trienes.
The ready availability of the starting materials and the
simplicity of the reaction conditions make this a very attractive
11 (a) C. M. Beaudry, J. P. Malerich and D. Trauner, Chem. Rev.,
2005, 105, 4757; (b) D. J. Tantillo, Annu. Rep. Prog. Chem., Sect.
B: Org. Chem., 2006, 102, 269.
12 C. L. Benson and F. G. West, Org. Lett., 2007, 9, 2545.
ꢀc
This journal is The Royal Society of Chemistry 2009
Chem. Commun., 2009, 2133–2135 | 2135