The enantiospecific synthesis of chromanes and isochromanes using a variant of an intramolecular Nicholas reaction

Article abstract of DOI:10.1016/j.tetlet.2012.05.112

The enantiospecific synthesis of chromanes and isochromanes obtained from an intramolecular Nicholas cyclisation reaction is discussed. During the course of this study we observed the formation of chroman-4-ones from a CAN deprotection step of a dioxolane and this is also discussed.

Full text of DOI:10.1016/j.tetlet.2012.05.112

Tetrahedron Letters 53 (2012) 4280–4282
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The enantiospecific synthesis of chromanes and isochromanes using a variant
of an intramolecular Nicholas reaction
⇑
Elizabeth Tyrrell , Khatebeh Mazloumi, Donatella Banti, Paulina Sajdak, Alex Sinclair, Adam Le Gresley
School of Chemistry and Pharmacy, Kingston University, Penrhyn Road, Kingston, Surrey, KT1 2EE, United Kingdom
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantiospecific synthesis of chromanes and isochromanes obtained from an intramolecular Nicholas
cyclisation reaction is discussed. During the course of this study we observed the formation of chroman-
4-ones from a CAN deprotection step of a dioxolane and this is also discussed.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 22 March 2012
Revised 14 May 2012
Accepted 23 May 2012
Available online 12 June 2012
Keywords:
Nicholas cyclisation
Chromane
Isochromane
Asymmetric alkynylation
N-Methylephedrine
Enantiospecific reaction
Previously we described the antihypertensive activity of a range
of novel chromanes,1 synthesised using a variation of an intramo-
lecular Nicholas reaction2 that has been developed, over a number
of years, in our laboratories.3 The assay involved isometric tension
recordings on segments of mouse thoracic aorta. After an initial
period of equilibration the tissues were contracted by application
Ph
CH3
O
N
O
F
F
F
OH
NC
CH3
CH3
CH3
O
of the
a-1-adrenoceptor stimulant, phenylephrine. Once the con-
traction had stabilised our compounds were evaluated by compar-
ing their ability to relax the pre-contracted tissue versus the
benchmark compound cromakalim (1).4 The best candidate (2) is
shown (Fig. 1).
1
2
F
Figure 1.
Although the derivatives that were synthesised retained some of
the pharmacophores, present in cromakalim (1), it was no surprise
that our best candidate 2 failed to replicate the same response as 1.
Ph
Ph
Ph
It was active at the 20
provided the same level of relaxation of the tissue at the 1
l
M scale compared to cromakalim 1 which
CH3
CH3
lM level.
F
2
F
F
F
It was observed, however, that when the same assay was carried
out in the presence of glibenclamide, a selective blocker of ATP-sen-
sitive K+ channels, chromane 2 continued to produce relaxation of
the contracted mouse thoracic tissue whereas cromakalim (1)
was ineffective. This observation therefore suggested two different
modes of action for these molecules.
CH3
CH3
O
O
O
F
Scheme 1.
The potassium channel modulating properties of cromakalim
(1) have been well documented.5 In collaboration with colleagues
at St. George’s Hospital Medical School we have been investigating
the possible modes of action of these novel chromanes. One line of
enquiry is the possibility that they may be involved in alternative
ion-selective membrane channels such as chloride channels. Com-
pared to potassium channels, the mechanisms of action of chloride
channels are less well understood despite the fact that they are
⇑
Corresponding author.
E-mail address: e.tyrrell@kingston.ac.uk (E. Tyrrell).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.112

E. Tyrrell et al. / Tetrahedron Letters 53 (2012) 4280–4282
4281
implicated in a wide range of physiological activities.6 As part of
O
O
R
R
our ongoing investigations into the structure–activity relationship
of 1 we were keen to determine the structural features that were
responsible for the selectivity we had observed. This would involve
the synthesis of simpler derivatives that might act as probes during
our investigations. Apart from the aryl substituents the main struc-
tural modification to be considered was the removal of the C-3
moiety to afford a chromane such as 3 (Scheme 1).
Another key aim in our ongoing screening investigations has
been the development of asymmetric variants of the Nicholas reac-
tion.7 Our approach to the synthesis of 3 was via aldehyde 5 which,
we reasoned, should be readily obtained from the deprotection of
dioxolane 4 (Scheme 2).
CAN, MeOH/MeCN
O
O
70 0
C
O
H
65 - 75%
4a R=H, 4b R=OMe, 4c R=Me
7a-c
OH
R
O
O
H
O
5a-c
6a-c
Scheme 3.
An asymmetric Carreira alkynylation8,9 of aldehyde 5 and cobalt
complexation followed by a Friedel-Crafts variant of the Nicholas
cyclisation10,11 should, after the oxidative decomplexation of dico-
balt hexacarbonyl, afford the desired chromane 3 in an enantiomeric
enriched form. Thus O-alkylation of phenol with 2-(2-bromoethyl)-
1,3-dioxane12 provided the corresponding dioxalane 4a (90%)
(Scheme 3). Our attempts to deprotect 4a were thwarted by variable
yields of the desired product 5a, substrate and decomposition prod-
ucts.13 A recent publication described the use of cerium ammonium
nitrate (CAN) for the deprotection of a wide range of dioxanes and
dioxolanes undermild conditions.14 Exposure of 4a toCAN15 led rap-
idly to the formation of a new product. Spectroscopic analysis failed
to reveal the desired aldehyde 5a, but instead showed the formation
of chroman-4-one 7a in a yield of 70%.
We reasoned that the origin of 7a was from 5a, via the alcohol 6a.
A survey of the literature confirmed that CAN oxidation of benzylic
alcohols to ketones (in the presence of TEMPO) is not without prec-
edent.16 Although unexpected, this serendipitous outcome, in terms
of an effective two-step formation of chroman-4-one 7a directly
from 4a in the presence of CAN, and an absence of a catalyst such
as TEMPO, may also be of synthetic interest.17 We were able to opti-
mise the production of aldehyde 5a (55–70%) by reducing the expo-
sure time of 4a to one equivalent of CAN for 20 min,18 any longer
would provide either 6a or 7a. Although the formation was a dis-
traction from our main aims we did investigate the production of
chromanones, 7b (75%) and 7c (78%) derived from p-methoxyphe-
nol and p-methylphenol, respectively.19 With the aldehyde 5a in
hand, we undertook the asymmetric alkynylation reaction. Previ-
ously, we revealed that both the yield of the Carreira asymmetric
alkynylation of aldehydes and the enantiomeric excess were vari-
able. For instance, the asymmetric alkynylation of benzaldehyde oc-
curred with a yield of 80% (ee 81%), p-bromobenzaldehyde 97% (ee
99%) and p-methoxybenzaldehyde 53% (ee 99%).20 Furthermore, the
reactions with non-aryl aldehydes were often slower, less efficient
and occurred with reduced enantioselectivities.21 Importantly,
however, it has been demonstrated that the stereochemical out-
come of the alkynylation reaction is dependent upon the choice of
chiral ligand.8,22 Thus the asymmetric alkynylation of aldehyde
5a, with phenylethyne in the presence of (+)-N-methylephedrine,
gave the corresponding propargyl alcohol 8a in a yield of 77% and
a disappointing enantiomeric excess of 50%. This result seems to
OH
O
O
O
H
R
5
8a R=Ph , 8b R=tolyl
Zn(OTf)
Et3
2
N
(+)- N-methylephedrine
HC
R
O
OH
O
O
H
R
9
10a R=Ph, 10b R=tolyl
10c R=benzyl
Scheme 4.
R
OH
i. Co2(CO)8
R2
ii. BF3.Et2O
iii CAN
R2
R1
R1
R
8a R=Ph, R1= O : R2= CH2
8b R=tolyl R1= O : R2= CH2
10a R=Ph, R1=CH2 : R2= O
10b R=tolyl, R1=CH2 : R2= O
10b R=benzyl, R1=CH2 : R2= O
11a
11b
12a
12b
12c
Scheme 5.
Table 1
Entry
Product
ee (%)
Product
ee (%)
(c.24 ee%)
1
2
3
4
5
8a
8b
10a
10b
10c
11b
50
74
81
82
77
73
11a
11b
12a
12b
12c
13b
45
71
77
82
76
71
90
95
95
100
99
97
i. K2CO3/KI
6a
O
O
H
O
O
a
ii.
Br
Obtained from the use of (ꢀ)-N-methylephedrine.
OH
O
4
represent an outlier as our subsequent data reveals. The use of 4-
ethynyltoluene provided 8b in 74% yield and an ee of 74%.23 The
same reaction performed upon the readily available aldehyde 9 pro-
vided propargyl alcohols 10a (89%, ee 81%), 10b (90%, ee 82%) and
10c (78%, ee 77%) (Scheme 4).
O
O
H
5
Scheme 2.

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E. Tyrrell et al. / Tetrahedron Letters 53 (2012) 4280–4282
6. Jentsch, T. J.; Stein, V.; Weinreich, F.; Zdebik, A. A. Physiol. Rev. 2002, 82, 503–
Propargyl alcohols 8a,b and 10a–c were then subjected to the
568.
Nicholas cyclisation reaction conditions (Scheme 5). This consisted
of complexation with dicobalt octacarbonyl (70–85%), reaction
with boron trifluoride diethyl etherate at ꢀ75 °C, to effect cyclisa-
tion, followed by decomplexation using CAN which provided the
corresponding chromanes 11a,b and isochromanes 12a–c in good
to excellent yields, that is 76% for 11a to 90% for 12a. The cyclised
products were analysed by chiral HPLC and our first example 8a,
with the lowest enantiomeric excess (50%), provided the corre-
sponding chromane 11a with an ee of 45% (90% corrected).24
The data for the other cyclisation products are provided (Table
1)25 which were all found to be consistently better than our proto-
type. Also included (entry 6), are data for 11b, that is, the antipode
to 10b.
The data summarised in Table 1 serve to confirm that, apart
from the outlier, (entry 1), the intramolecular Nicholas cyclisation
reaction provides chiral chromanes and isochromanes from chiral
substrates with a minimum loss in optical activity. During the
course of these investigations, we additionally identified an effi-
cient synthesis of chroman-4-ones from the CAN-mediated depro-
tection of a dioxolone.26 Although the biological activity of the
chromanes and isochromanes that were synthesised during the
course of this study are currently underway, obtaining answers
to the challenging questions such as the stereochemical relation-
ships between the substrates and products continues to remain a
high priority in our group.
7. Unpublished results: Tyrrell, E.; Brawn, P.; Carew, M.; Greenwood, I.
Tetrahedron, pending submission.
8. Franz, D. E.; Fassler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, 1806–1807;
Franz, D. E.; Fassler, R.; Tomooka, C. S.; Carreira, E. M. Acc. Chem. Res. 2000, 33,
373–381; Sasaki, H.; Boyall, D.; Carreira, E. M. Helv. Chim. Acta. 2001, 84, 964–
971.
9. Tyrrell, E. Curr. Org. Chem. 2009, 13, 1540–1552.
10. Muehldorf, A. V.; Guzman-Perez, A.; Kluge, A. F. Tetrahedron Lett. 1994, 35,
8755–8758.
11. Grove, D. D.; Miskevich, F.; Smith, C. C.; Corte, J. R. Tetrahedron Lett. 1990, 64,
6277–6280.
12. We also made the corresponding dioxolane derivative.
13. Kocienski, P.J., Protecting Groups, 2000, Thieme Verlag, Stuttgart. Classic acid
hydrolysis failed and other methods proved equally unreliable, that is catalytic
iodine: Sun, J.; Dong, L.; Cao, L.; Wang, X.; Wang, S.; Hu, Y. J. Org. Chem. 2004,
69, 8932–8934.
14. Maulide, N.; Vanherck, J.-C.; Gautier, A.; Marko, I. E. Acc. Chem. Res. 2007, 40,
381–393.
15. Dissolved in a 2:1 mixture of acetonitrile/water at 70 °C for 20 min.
16. Kim, S. S.; Jung, H. C. Synthesis 2003, 2135–2137.
17. Benzopyranone syntheses via a Stetter reaction: Enders, D.; Breuer, K.; Runsink,
J. Helv. Chim. Acta. 1996, 79, 1899–1902; Rong, Z. Q.; Li, Y.; Yang, G.-Q.; You, S-.
L. Synlett 2011, 1033–1037; Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2005,
127, 6284–6289; He, J.; Zheng, J.; Liu, J.; She, X.; Pan, X. Org. Lett. 2006, 8, 4637–
4640. and other references cited therein.
18. Aldehyde
5 was frequently contaminated with 6 and therefore required
purification which reduced the yield further.
19. These investigations were carried out by P.S. as part of a summer internship.
20. Tyrrell, E.; Tesfa, K.-H.; Mann, A.; Singh, K. Synthesis 2007, 1491–1498.
21. Tyrrell, E.; Tesfa, K.-H.; Millet, J.; Muller, C. Synthesis 2006, 3099–3105.
22. Anand, N. K.; Carreira, E. M. J. Am. Chem. Soc. 2001, 123, 9687–9688.
23. Chiral HPLC was carried out using a (Chiralcel-OD-H column) with a Perkin
Elmer 200 EP photodiode array diode detector. Measurements were made at
220 nm at a flow rate of 0.3 ml/min. Solvent, hexane/IPA (90/10).
Acknowledgments
24. The corrected enantiomeric excess10 is determined as the ee of the product
divided by the ee of the substrate expressed as a percentage.
25. All new compounds gave satisfactory spectroscopic data.
The authors thank the EPSRC National Mass Spectrometry Ser-
vice Centre, University of Swansea for High Resolution Mass Spec-
tra. We express our gratitude to the University of I.A.U. (Iran) for
the generous provision, in the form of a studentship, to K.M., and
to Kingston University for providing the financial support for the
summer internship to P.S.
26. Representative procedure: 2,3-dihydro-4H-chromen-4-one (7a). To the
dioxalane 4a (1.20 g, 6.18 mmol) in an MeCN–H2O mixture (10 ml, 1:2) was
added CAN (5 g, 9.27 mmol). The mixture was heated to 70 °C, with stirring, for
30 min and then allowed to cool to ambient temperature. The organic solvent
was partitioned in H2O and extracted with Et2O (3 ꢁ 20 mL). The combined
organic layer was washed with a saturated solution of NaHCO3 (20 mL) and
then dried over anhydrous MgSO4. Filtration in vacuo gave the title compound
as a yellow oil 0.64 g, 70%. mmax (neat)/cmꢀ1 2923, 1688, 1603, 1479, 1299,
1255, 1119, 1039, 870, 765; 1H NMR (400 MHz, CDCl3) d 7.90 (1H, dd, J = 7.85,
1.73 Hz, Ph), 7.50 (1H, ddd, J = 8.41, 7.16, 1.72 Hz, Ph), 7.05 (1H, ddd, J = 8.04,
7.05, 0.32 Hz, Ph), 6.97 (1H, dd, J = 8.03, 0.32 Hz, Ph), 4.56 (2H, t, J = 6.46 Hz,
OCH2CH2), 2.82 (2H, t, J = 6.46 Hz, OCH2CH2CO); 13C NMR (100 MHz, CDCl3)
191.86 (CO), 161.88, 136.02, 127.18, 121.41, 121.38, 117.91, 67.04 (OCH2),
37.82 (CH2CH2CO): HRMS (EI, M+) calcd for C9H8O2 148.0519; found 148.0520.
Data for 4-(phenylethynyl)-3,4-dihydro-2H-chromene (11a).
References and notes
1. Tyrrell, E.; Tesfa, K.-H.; Greenwood, I.; Mann, A. Bioorg. Med. Chem. Lett. 2008,
18, 1237–1240.
2. Nicholas, K. M. Acc. Chem. Res. 1987, 20, 207–214; For a review please see:
Fletcher, A. J.; Christie, S. D. R. J. Chem. Soc., Perkin Trans. 1 2000, 11, 1657–1668;
Teobold, B. J. Tetrahedron 2002, 58, 4133–4170.
3. Berge, J.; Claridge, S.; Mann, A. L.; Muller, C.; Tyrrell, E. Tetrahedron Lett. 1997,
38, 685–686; Tyrrell, E.; Millet, J.; Tesfa, K.-H.; Williams, N.; Mann, A. L.; Tillett,
C.; Tyrrell, E. Tetrahedron 2007, 63, 12769–12778; Mann, A. L.; Muller, C.;
Tyrrell, E. J. Chem. Soc., Perkin Trans. 1 1998, 1427–1438.
4. For reviews of cromakalim, see: Roxburgh, C. J. Synthesis 1996, 307–320;
Sebille, S.; De Tullio, P.; Boverie, S.; Antoine, M. H.; Lebrun, P. B. Curr. Med.
Chem. 2004, 11, 1213–1222.
½
a 2D0
ꢂ
ꢀ38 (c 1, Et2O) mmax (neat)/cmꢀ1 2976, 2846, 2060, 2031, 1610, 1600,
1501, 1457, 1230, 1120, 1070, 1021, 765; 1H NMR (400 MHz, CDCl3) d 7.35–
7.27 (3H, m,Ph), 7.27-7.13 (3H, m, Ph), 7.07–7.00 (1H, m, Ph), 6.83–6.77 (1H, m,
Ph), 6.75–6.72 (1H, m, Ph), 4.32–4.25 (1H, m, OCH2), 4.14–4.06 (1H, m, OCH2),
3.95 (1H, t, J = 6.18 Hz, CH), 2.26–2.04 (2H, m, CH2): 13C NMR (100 MHz, CDCl3)
153.93, 131.74, 129.86, 128.45, 128.31, 128.04, 123.43, 121.88, 120.64, 117.07,
91.31, 82.21, 64.44, 29.16, 28.13: HRMS (EI, M+) calcd for C17H14O 234.1039;
found 234.1044: HPLC (Chiralcel-OD-H column, hexane/IPA 10%, 254 nm):
tR = 8.58 (major), 16.73 min (minor).
5. Hamilton, T. C.; Weir, S. W.; Weston, A. H. Br. J. Pharmacol. 1986, 88, 103–112;
Ashcroft, F. M.; Gribble, F. M. Trends Pharm. Sci. 2005, 21, 439–444; Cechetti, V.;
Tabarrini, O.; Sabatini, S. Curr. Top. Med. Chem. 2006, 6, 1049–1068.