Kinetic diastereoselection of homoallylic indium alkoxides: Syn crotylation of arylaldehydes

Article abstract of DOI:10.1055/s-1998-1804

Reaction of crotylindium sesquibromide with benzaldehyde in DMF at 20°C affords syn-1-phenyl-2-methylbut-3-enol (ca. 40 % de) after aqueous acidic work-up. At 22°C in DMF, prior to work-up a greater relative proportion of the anti intermediate is decompos

Full text of DOI:10.1055/s-1998-1804

August 1998
SYNLETT
903
Kinetic Diastereoselection of Homoallylic Indium Alkoxides: Syn Crotylation of
Arylaldehydes
Guy C. Lloyd-Jones* and Tim Russell
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, UK
Fax +44(117)929 8611; E-mail guy.lloyd-jones@bristol.ac.uk
Received 1 May 1998
Abstract: Reaction of crotylindium sesquibromide with benzaldehyde
in DMF at 20 °C affords syn-1-phenyl-2-methylbut-3-enol (ca. 40 % de)
after aqueous acidic work-up. At 22 °C in DMF, prior to work-up a
greater relative proportion of the anti intermediate is decomposed as
compared to its syn diastereomer. The resultant kinetic
diastereoselection upgrades, the syn / anti ratio to 99 / 1 with a
concomitant drop in overall yield.
1
Recently, indium-mediated aqueous “Barbier-type allylation” of
2
ketones and aldehydes has received much attention. The reaction is
often high yielding and convenient. When crotylbromide is employed,
the reaction is highly regioselective: for example, benzaldehyde affords
3
2-methyl-1-phenylbut-3-en-1-ol 2a exclusively, Scheme 1. Isaac and
3a
Chan
have examined a range of aldehyde / allylic bromide
combinations and of these, crotyl bromide / benzaldehyde was the only
non-diastereoselective pair - indeed all other combinations afforded the
anti diastereomer in 36 - 92 % de. These reactions have been proposed
to proceed by formation of crotylindium species which then react with
the aldehyde via Zimmermann-Traxler type transition states. Whilst
this conveniently explains the regioselectivity, it is somewhat surprising
(entry 4, conditions C). However, this reduced the selectivity somewhat
(65 % syn) and we therefore returned to employing the crotylindium
sesquibromide reagent and sought methods to improve the syn-
selectivity.
3a
that there is no diastereoselectivity with benzaldehyde (1 / 1 syn / anti).
The reaction between crotylindium sesquibromide and benzaldehyde in
DMF occurs rapidly - indeed no benzaldehyde could be detected by
TLC immediately after addition of the aldehyde to a 0 °C DMF solution
of the crotylindium sesquibromide. Reactions quenched at this point by
addition of 1M HCl (aq) gave excellent isolated yields of 2a (entry 3).
However, it became evident that if the reaction mixture was not
quenched immediately, some decomposition products could be detected
in the 1H NMR of the crude reaction product.
Scheme 1
The ratio of syn / anti 2a was also variable and furthermore, the extent
of decomposition was dependent upon both the ratio of indium /
crotylbromide employed to prepare the crotylindium reagent and the
time that the reaction mixture was left before quenching. When an
excess of reagent was employed and then the reaction mixture left for 96
h at RT, the syn / anti ratio of 2a was dramatically increased from the
initial (73 / 27) to > 99 / 1.
4
InCl3-promoted Sn-mediated conditions
diastereoselectivity as does use of In(I) iodide in THF. Indeed, the only
example of diastereoselectivity for the indium-mediated reaction of
also fail to induce
5
6
crotyl bromide with benzaldehyde is reported by Butsugan et al. who
also employed Barbier-type conditions but employed anhydrous DMF
instead of water and obtained 2a with low selectivity for the syn isomer
(16-32 % de). We were thus intrigued as to whether this moderate syn
selectivity could be improved upon.
The variations in diastereoselectivity / final diastereomeric excess could
occur by a number of processes - Figure 1. For example, the formation
of the intermediates - assumed to be indium homoallylic alkoxide
species (1a) - could be reversible (Mode I). Alternatively, the addition
could be irreversible but species (1a) could epimerise e.g. by
deprotonation-reprotonation at the benzylic or allylic positions (Mode
II). In either case the initial 73 / 27 ratio of syn to anti is the result of a
kinetic allylation whilst the final ratio would be the thermodynamic
product mixture. Other possibilities include selective decomposition of
the intermediate indium homoallylic alkoxide species (1a). If this
effected a kinetic diastereoselection of anti 1a then a higher proportion
of the syn alcohol 2a would be obtained on quenching (Mode III).
Herein we report on the effect of reaction conditions on the syn -
selective addition of crotylindium sesquibromide to benzaldehyde,
Table 1. First we repeated the aqueous In-mediated Barbier type
crotylation reported by Isaac and Chan (entry 1, conditions A) and
then compared this with the use of pre-formed crotylindium
sesquibromide reagents in DMF (entries 2, 3 and 4).
3a
The crotylation reactions in DMF afforded 2a with moderate syn-
selectivity (73 - 78 %, entries 2 and 3, conditions B) Notably, with
preformed reagent, the syn selectivity is higher than when “Barbier”
6
7
type conditions are employed (58 - 66 % syn). Recently, we and
To investigate the possibilities shown in Fig. 1, we added benzaldehyde
to crotylindium sesquibromide in DMF at 20 °C and then took samples
at various time intervals. The samples were quenched by addition to a
large volume of 1M HCl, extracted with ether, concentrated and then
8
others have reported that addition of alkoxide or halide to allylindium
species (to form “ate” complexes) can usefully modify allylindium
reagents and we thus examined the crotylindium “ate” complex
generated by addition of LiBr to crotylindium sesquibromide in DMF
1
analysed by H NMR. The percentage yield of 2a and diastereomeric

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SYNLETT
excess are presented graphically in Fig 2. Interestingly, the rate of
decomposition of the syn intermediate parallels that of the anti
intermediate and thus as the concentration of anti -1a nears zero, the
ratio of decomposition of syn-1a slows dramatically - although not
9
completely. These results are most consistent with Mode III - but do
not completely rule out Modes I or II or other possibilities. Nonetheless,
since the upgrading of the diastereomeric excess occurs by near-
complete decomposition of the anti- versus the syn intermediate the
initial ratio of syn to anti 1a limits the ultimate yield of
diastereomerically pure syn 2a. Having noticed a small increase in the
syn / anti ratio when the benzaldehyde was added at 0 °C (78 / 22 versus
73 / 27 at 22 °C. Table 1, entries 2,3) we tried to improve the procedure
by adding the benzaldehyde at -78 °C and then, after 1h, heated the
reaction mixture to 60 °C for 2 h. Under these conditions, the isolated
yield of syn crotylation product was low (24 % ) but with a de in excess
of 99 %. A control experiment indicated the initial syn / anti selectivity
at -78 °C was lower (60 / 30) than at 22 °C (73 / 27). We thus returned to
addition at 0 °C and ageing at 22 °C (Scheme 2; Table 2, entry 1). Under
these conditions two other aryl aldehydes gave analogous products (2b
11
and 2c) in moderately high de (syn ), Table 2, entries 2 and 4, albeit
with lower final yields. For comparison, we also performed these
reactions under aqueous In-mediated Barbier type conditions (entries 3
and 5). In conclusion, we have shown how the conditions employed for
the reaction of simple aromatic aldehydes with crotylindium
sesquibromide complex in DMF can dramatically affect both the final
yield and diastereomeric excess. These reactions afford products with
high syn / anti ratios through an initial moderately syn-selective
10
addition and a subsequent decomposition that upgrades the de
substantially. Further studies are in progress and will be reported in due
course.
Acknowledgements. G.C.L-J thanks the Zeneca Strategic Research
Fund for generous support.
References and Notes
(1) Barbier type allylation refers to reactions in which the carbonyl,
metal and allylic halide are reacted simultaneously. This may
proceed via formation of radical ion pairs rather than via genuine
allylmetal species. T. H. Chan, C. J. Li, M. C. Lee, Z. Y. Wei, Can.
J. Chem., 1994, 72, 1181-1192.
(2) For leading recent references see: M. B. Isaac, L. A. Paquette, J.
Org. Chem., 1997, 62, 5333-5338; see also X.-H. Yi, Y. Meng, C.-
J. Li, Tetrahedron Lett., 1997, 38, 4731-4734; T.-P. Loh, X. R. Li,
Angew. Chem., Int. Ed. Engl., 1997, 36, 980-982. For reviews see:
C.-J. Li, Tetrahedron, 1996, 52, 5643-68; idem, Chem. Rev., 1993,
93, 2023-35; P. Cintas, Synlett, 1995, 1087-1096.
Scheme 2

August 1998
SYNLETT
905
(3) a) M. B. Isaac, T. H. Chan, Tetrahedron Lett., 1995, 36, 8957-
8960; b) S.-C. H. Diana, K.-Y. Sim, T.-P. Loh, Synlett, 1996, 263-
264; c) T. H. Chan, M. B. Isaac, Pure & Appl. Chem., 1996, 68,
919-924.
through open transition states for which the syn product is
expected.
(11) Diastereomeric identities of 2a, b and c were assigned by analysis
3
of the J HH benzylic-allylic coupling constants in CDCl3 solution
(4) X.-R. Li, T.-P. Loh, Tetrahedron: Asymmetry, 1996, 7, 1535-1538.
(syn, 5.5, 5.7 and 5.4 Hz; anti, 7.9, 8.1 and 7.7 Hz respectively). 2-
Methyl-1-phenylbut-3-en-1-ol
2a
and
2-methyl-1-(p-
(5) S. Araki, H. Ito, N. Katsumara, Y. Butsugan, J. Organometal.
Chem., 1989, 369, 291-296.
methoxyphenyl)but-3-en-1-ol 2b are known compounds (2a, U.
Schöllkopf, K. Fellenberger, M. Rizk, Liebigs Ann. Chem., 1970,
734, 106-115; 2b, J. P. Takahara, Y. Masuyama, Y. Kurusu, J. Am.
Chem. Soc., 1992, 114, 2577-2586). 2-Methyl-1-(β-naphthyl)but-
3-en-1-ol 2c: 1H NMR (300 MHz) syn-2c: 7.68-7.82 (m, 4H,
arom. H); 7.35-7.47 (m, 4H, H arom.); 5.75 (ddd, 3J = 17.7, 10.7,
(6) S. Araki, H. Ito, Y. Butsugan, J. Org. Chem., 1988, 53, 1831-33.
(7) S. M. Capps, G. C. Lloyd-Jones, M. Murray, T. M. Peakman, K. E.
Walsh; Tetrahedron Lett., 1998 39, 2853-2856; H. A. F. Höppe, G.
C. Lloyd-Jones, M. Murray, T. M. Peakman, K. E. Walsh; Angew.
Chem., Int. Ed. 1998, 110, 1545.
7.2, 1H, CH=); 5.02 (ddd, 2J = 1.1, J = 17.7, 4J = 1.1, 1H, =CH2
3
trans), 5.01 (ddd, 2J = 1.1, 3J = 10.7, 4J = 1.1, 1H, =CH2 cis); 4.69
(d, 3J = 5.4, 1H, CH(OH)), 2.63 (ddddq, 3J = 7.2, 6.8, 5.4, 4J = 1.1,
1.1, 1H, CH(Me)), 2.27 (bs, 1H, OH), 1.00 (d, 3J = 6.8, 3H, CH3);
anti-2c: 7.68-7.82 (m, 4H, arom. H); 7.35-7.47 (m, 4H, H arom.);
5.77 (ddd, 3J = 17.1, 11.7, 8.1, 1H, CH=); 5.19 (ddd, 2J = 1.1, 3J =
17.1, 4J = 1.9, 1H, =CH2 trans), 5.16 (ddd, 2J = 1.1, 3J = 11.7, 4J =
1.1, 1H, =CH2 cis); 4.47 (d, 3J = 7.7, 1H, CH(OH)), 2.55 (ddddq,
3J = 8.1, 7.7, 6.8, 4J = 1.9, 1.1, 1H, CH(Me)), 2.40 (bs, 1H, OH),
(8) M. T. Reetz, H. Haning, J. Organometal. Chem., 1998, 541, 117-
120. For tetraorganoindates see: S. Araki, S.-J. Jin, Y. Butsugan, J.
Chem. Soc., Perkin Trans. 1, 1995, 549-552.
(9) We are currently trying to ascertain what the decomposition
products are. We note that the major rotamer of the benzyl-allylic
C-C bond in the anti intermediate is likely to be that in which the
internal alkenyl carbon is antiperiplanar to the C-OIn bond -
decomposition may involve cyclopropyl type intermediates - see
ref 7. Also excess crotyl bromide and indium is necessary. As
noted, the rate of decomposition of syn-1a may be kinetically
linked to anti-1a. A much more detailed kinetic investigation is in
progress and will be reported in full in due course.
0.86 (d, J = 6.8, 3H, CH3); 13C NMR (75 MHz) syn-2c 140.5
3
(CH=); 140.0 (C(2)arom.); 133.0, 132.8 (2 x C-arom.) ; 127.9,
127.7, 127.6, 125.9, 125.2, 124.6 (7 x CH-arom.); 115.5 (=CH2);
77.4 (C(OH); 44.5 (CH(Me)); 14.0 (CH3); anti-2c; 140.5 (CH=);
139.8 (C(2)-arom.), 133.1, 133.0 (2 x C-arom.) ; 128.0, 127.8,
127.6, 126.0, 125.8, 125.7, 124.6 (7 x CH-arom.); 116.8 (=CH2);
77.9 (C(OH); 46.0 (CH(Me)); 16.5 (CH3); IR(NaCl) 3415 (νOH);
(10) The Z-crotyl anion is thermodynamically favoured over the E-
-1
form (∆GZ/E = 4 kcal mol , M. Schlosser, J. Hartmann, J. Am.
Chem. Soc., 1976, 98, 4674-4676). However, due to low
polarisation of the C-In bond E-crotylindium is expected to be
favoured and would afford anti-crotylation products on reaction
with arylaldehydes via Zimmermann-Traxler type transition
states. We suggest that the crotylations discussed here occur
+
1270 (νC-O) cm-1; MS(EI) 212 (M ,1); 194 (2); 179 (11); 157 (90);
129 (100); C15H16O, 212.29, requires C, 84.87; H, 7.60 %; found
C, 84.50; H 7.94 %.