The conversion of carbonyl compounds into pentadienylamines by a Julia-Kocienski olefination procedure

Article abstract of DOI:10.1055/s-2008-1078011

Julia-Kocienski olefination has been successfully employed to convert carbonyl compounds into the corresponding Boc-protected 1,3-pentadienyl amines in a C₄N homologation process. Good to excellent yields are achieved in THF using MHMDS as base to deprotonate the precursor 1-phenyl-1H-tetrazol-5- ylsulfone reagent. The nature of the metallic countercation dramatically affects the stereoselectivity of the newly formed alkene: good levels of 2E,4E-stereoselectivity are achieved using KHMDS whereas LiHMDS gives a predominance of the 2E,4Z-dienyl product. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078011

LETTER
2183
The Conversion of Carbonyl Compounds into Pentadienylamines by a Julia–
Kocienski Olefination Procedure
Conversion of
C
a
e
rbonyl Com
y
pounds into
h
Pentadienyl
a
amine
s
n Bastin, Mélanie Liron, Richard J. K. Taylor*
Department of Chemistry, University of York, Heslington, York, YO10 5DD, UK
Fax +44(1904)434523; E-mail: rjkt@york.ac.uk
Received 23 June 2008
Dedicated to Professor Sir Jack Baldwin, FRS in celebration of his 70th birthday
griseoviridin (1),1 and virginiamycin M1 (2),2 the antibiot-
Abstract: Julia–Kocienski olefination has been successfully em-
ployed to convert carbonyl compounds into the corresponding Boc-
protected 1,3-pentadienyl amines in a C4N homologation process.
Good to excellent yields are achieved in THF using MHMDS as
ic aurodox (3),3 and the antitumour, antibiotic oxazolomy-
cin family [e.g., oxazolomycin A (4)4 and neooxa-
zolomycin (5)5], as well as more recently discovered ex-
base to deprotonate the precursor 1-phenyl-1H-tetrazol-5-ylsulfone amples.6
reagent. The nature of the metallic countercation dramatically af-
For our own synthetic approach to the oxazolomycin fam-
fects the stereoselectivity of the newly formed alkene: good levels
of 2E,4E-stereoselectivity are achieved using KHMDS whereas
LiHMDS gives a predominance of the 2E,4Z-dienyl product.
ily,7 we required a procedure for the homologation of al-
dehydes such as 6 into the corresponding penta-1,3-dienyl
N-Boc amines 7, as shown in Scheme 1. Initially, we in-
vestigated the Horner–Wadsworth–Emmons reagent 8,
developed by Connell and Helquist,8 and applied to a wide
range of aliphatic aromatic, and heteroaromatic carbonyl
compounds to afford the desired homologated products
with a high E,E-stereoselectivity in moderate to good
yields (47–74%). However, in our hands, applying this
Key words: 1,3-pentadienyl amines, modified Julia olefination,
alkenes, 1-phenyl-1H-tetrazol-5-yl sulfones
The 5-aminopenta-1,3-dienyl moiety is found in a number
of naturally occurring compounds with interesting biolog-
ical activities (Figure 1). These include the antibiotics
O
OH
O
O
H
N
O
N
H
O
S
O
O
H
N
O
O
N
H
O
N
OH
O
N
OH
O
griseoviridin (1)
virginiamycin M1 (2)
Me
N
Me
Me
OH
O
O
OH
Me
O
OMe
H
H
Me
O
H
N
O
Me
HO OH
Me
Me
OH
OH
aurodox (3)
O
O
N
N
Me
Me
O
Me
O
OMe
Me
O
O
O
N
HO
N
H
O
HO
H
OH
HO
Me
HO
Me
NMe
NMe
OH
OH
oxazolomycin A (4)
neooxazolomycin A (5)
O
O
Figure 1 Natural products containing the 5-aminopenta-1,3-dienyl unit
SYNLETT 2008, No. 14, pp 2183–2187
2
2
.0
8
.2
0
0
8
Advanced online publication: 31.07.2008
DOI: 10.1055/s-2008-1078011; Art ID: D22108ST
© Georg Thieme Verlag Stuttgart · New York

2184
R. Bastin et al.
LETTER
NHBoc
(EtO)2P(O)
8
OTBS
NaHMDS (2.2 equiv), THF
–78 °C to r.t.
OTBS
4
2
O
NHBoc
45% (2E,4E/2Z,4E = 4:1)
7
6
Scheme 1
i. (Boc)2NH, NaH
DMF, 60 °C, 3 h
98%
PT
NHBoc
PT
S
NHBoc
Cl
S
Cl
ii. (NH4)6Mo7O24⋅4H2O
ii. PTSH, NaH
THF, r.t., 7 h
92%
O2
H2O2
11
9
10
EtOH, r.t., 1 h
95%
iii. TFA, PhOMe
THF, 30 min
95%
Ph
N
N
N
PTSH =
SH
N
Scheme 2
methodology to model aldehyde 6 gave a disappointing presence of a catalytic amount of ammonium molybdate
45% yield of the pentadienyl amine 7 as a mixture of diene tetrahydrate13 then gave the required sulfone 11 as a crys-
stereoisomers (Scheme 1).
talline solid in 96% yield,14 without the complication of
allylic rearrangements often encountered in the oxidation
of allylic sulfides of this type.15
In view of this disappointing result, we decided to inves-
tigate the use of the Julia–Kocienski olefination (a type of
modified Julia olefination, MJO) for the transformation The initial evaluation study involved the treatment of sul-
depicted in Scheme 1. Sylvestre Julia and his group orig- fone 11 with sodium hexamethyldisilazide (NaHMDS)
inally reported the one-pot synthesis of alkenes using and subsequent addition of benzaldehyde (Scheme 3), us-
lithiated 2-benzothiazolyl sulfones (BT-sulfones) and car- ing the same conditions employed by Connell and
bonyl compounds in 1991,9 and since then several groups Helquist with the corresponding phosphonate reagent 8.
have expanded the scope of this process and improved its These conditions gave the expected alkenes 12 in 61%
stereoselectivity.10–12 Solvent effects have proved to be yield as a 1:1 mixture of alkene isomers about the newly
extremely important, and major advances have come from formed double bond (in contrast to Helquist’s procedure,8
modifying the heterocyclic activating group. The intro- no isomerisation of the pre-existing double bond in E-sul-
duction of the 1-phenyl-1H-tetrazol-5-yl (PT) group by fone 11 was observed under these conditions).
Kocienski et al. has proved to be particularly valuable giv-
We went on to optimise this Julia–Kocienski olefination
en the enhanced stability of the metalated sulfones, the ef-
in terms of solvent, temperature, base, and the order of ad-
ficiency of the homologation with a range of substrates,
dition. The use of THF at –78 °C was preferred and it was
then established that the choice of base was important
and the high stereoselectivities observed.10
Herein, we report the preparation of a PT-sulfonyl reagent (Scheme 3). According to the literature, the trans selectiv-
equivalent to the Helquist reagent 8 and its use for the con- ity of the reaction involving PT-sulfones increases with
version of carbonyl compounds into 1,3-pentadienyl N- the electropositivity of the countercation of the base (K >
Boc amines (and the corresponding deprotected amines); Na > Li).10 The use of KHMDS gave diene 12 in almost
the dramatic effect of the metallic countercation on the quantitative yield although the E/Z ratio remained 1:1.
stereoselectivity of the Julia–Kocienski reaction is also However, greater E,E-stereoselectivity was obtained
discussed.
(63:37) when the preformed sulfonyl dianion was added
to the benzaldehyde, and this was improved still further
(72:28) when an equimolar amount of 18-crown-6 (18-cr-
6) was employed.
The PT-sulfone 11 required for the Julia–Kocienski reac-
tion, was easily prepared in four steps from commercially
available (Fluka) trans-1,4-dichlorobut-2-ene (9;
Scheme 2). Thus, treatment of dichloride 9 with di-tert- In dramatic contrast, changing to LiHMDS gave the most
butyl iminodicarboxylate and NaH in DMF, followed by stereoselective process of all resulting in a predominance
treatment of the product with commercially available 1- of the 2E,4Z-diene isomer (E,E/E,Z = 13:87).16,17
phenyl-1H-tetrazol-5-thiol in THF in the presence of so-
dium hydride, and then removal of one of the Boc protect-
ing groups using TFA produced sulfide 10 in high overall
yield with no detectable isomerisation of the double bond.
Sulfide oxidation using aqueous hydrogen peroxide in the
We next went on to examine the scope of this process with
a range of aromatic, heterocyclic, vinylic, and aliphatic al-
dehydes (Table 1, entries 1–11).18 In almost all cases, bet-
ter yields were observed with LiHMDS compared to
Synlett 2008, No. 14, 2183–2187 © Thieme Stuttgart · New York

LETTER
Conversion of Carbonyl Compounds into Pentadienylamines
2185
Table 1 Reactions of Sulfone 11 with Aldehydes and Ketones Using KHMDS or LiHMDS
i. MHMDS (2.1 equiv)
THF, –78 °C
ii. R1R2CO, THF
–78 °C to r.t.
R1
NHBoc
PT
NHBoc
S
O2
R2
11
12–23 and 7
Entry R1R2CO
Product
KHMDSa,b
LiHMDSb
2E,4E/2E,4Z
Yield (%)
72
2E,4E/2E,4Z
Yield (%)
1
2
PhCHO
72:28
70:30
13:87
13:87
72
91
Ph
NHBoc
12
75
75
63
86
67
CHO
NHBoc
MeO
MeO
Cl
13
3
4
5
6
77:23
80:20
75:25
80:20
23:77
16:84
25:75
65:35
86
82
95
65
CHO
NHBoc
NHBoc
Cl
14
CHO
F3C
F3C
NC
15
CHO
CHO
NHBoc
NHBoc
NC
16
O2N
O2N
Ph
17
7
8
>95:5
84:16
59
75
23:77
34:66
88
59
CHO
Ph
NHBoc
18
CHO
NHBoc
O
O
19
9
C5H11CHO
71:29
78:22
78
73
29:71
63:37
80
76
C5H11
NHBoc
NHBoc
20
10
CHO
21
22
11
12
>95:5
n/a
23
76
>95:5
n/a
88
94
CHO
NHBoc
NHBoc
O
23
13c
>95:5c
93
–
–
OTBS
OTBS
O
NHBoc
6
7
a In all reactions using KHMDS, 1.2 equiv of 18-crown-6 was added to the mixture.
b Unless stated otherwise, the preformed dianion was added by cannula to the carbonyl compound.
c Using NaHMDS with the aldehyde added to the preformed dianion.
KHMDS and, again, KHMDS gave a predominance of the ceptions in terms of LiHMDS stereoselectivity were p-ni-
newly formed E-alkene whereas LiHMDS generally gave trobenzaldehyde (entry 6) and hindered, a-branched
a predominance of the newly formed Z-alkene. Three ex- aliphatic aldehydes (entries 10 and 11) where the newly
Synlett 2008, No. 14, 2183–2187 © Thieme Stuttgart · New York

2186
R. Bastin et al.
LETTER
i. MHMDS (2.1 equiv), THF
–78 °C, 30 min
2
4
NHBoc
PT
NHBoc
Ph
NHBoc
+
S
ii. PhCHO,
–78 °C to r.t.
O2
Ph
11
12
M = Na, 61% (2E,4E/2E,4Z = 50:50)
M = K, 97% (2E,4E/2E,4Z = 50:50)
M = K (+ 18-cr-6), 72% (2E,4E/2E,4Z = 72:28)
M = Li, 72% (2E,4E/2E,4Z = 13:87)
Scheme 3
TFA, PhOMe
CH2Cl2,
r.t., 30 min
MeCO2Cl, Et3N
CH2Cl2, r.t., 1 h
Ph
NHBoc
Ph
NH2
Ph
NHCO2Me
98%
90%
12
(E,E/E,Z = 72:28)
24
25
(E,E/E,Z = 72:28)
(E,E/E,Z = 72:28)
Scheme 4
formed E-alkene predominated. In the extreme case of
pivaldehyde, only the E-isomer could be observed by 1H
NMR spectroscopy (entry 11). Cyclohexanone proved a
good substrate (entry 12) but, in contrast to phosphonate
reagent 8, other ketones (acetophenone, benzophenone,
pinacolone, diethyl ketone) gave little or none of the ho-
mologated products. Finally, in Table 1 (entry 13), the
original reaction (Scheme 1) was repeated using sulfone
11; we were delighted to observe that, again using Na-
HMDS, the required adduct 7 was now obtained in almost
quantitative yield as the E,E-isomer.
References and Notes
(1) Dvorak, C. A.; Schmitz, W. D.; Poon, D. J.; Pryde, D. C.;
Lawson, J. P.; Amos, R. A.; Meyers, A. I. Angew. Chem. Int.
Ed. 2000, 39, 1664; and references therein.
(2) Kingston, D. G. I.; Kolpak, M. X.; LeFevre, J. W.; Borup-
Grochtmann, I. J. Am. Chem. Soc. 1983, 105, 5106.
(3) Maehr, H.; Leach, M.; Williams, T. H.; Blount, J. F. Can. J.
Chem. 1980, 58, 501.
(4) Mori, T.; Takahashi, K.; Kashiwabara, M.; Uemura, D.;
Katayama, C.; Iwadare, S.; Shizuri, I.; Mitomo, R.; Nakano,
F.; Matsuzaki, A. Tetrahedron Lett. 1985, 26, 1073.
(5) Takahashi, K.; Kawabata, M.; Uemura, D.; Iwadare, S.;
Mitomo, R.; Nakano, F.; Matsuzaki, A. Tetrahedron Lett.
1985, 26, 1077.
(6) (a) Ryu, G.; Kim, S.-K. J. Antibiot. 1999, 52, 193.
(b) Otani, T.; Yoshida, K.-I.; Kubota, H.; Kawai, S.; Ito, S.;
Hori, H.; Ishiyama, T.; Oki, T. J. Antibiot. 2000, 53, 1397.
(c) Manam, R. R.; Teisan, S.; White, D. J.; Nicholson, B.;
Grodberg, J.; Neuteboom, S. T. C.; Lam, K. S.; Mosca, D.
A.; Lloyd, G. K.; Potts, B. C. M. J. Nat. Prod. 2005, 68, 240.
(7) (a) Papillon, J. P. N.; Taylor, R. J. K. Org. Lett. 2000, 2,
1987. (b) Papillon, J. P. N.; Taylor, R. J. K. Abstracts of
Papers, 222nd Meeting of the American Chemical Society,
Chicago IL, Aug 26–30, 2001; American Chemical Society:
Washington DC, 2001. (c) Papillon, J. P. N.; Taylor, R. J. K.
Org. Lett. 2002, 4, 119. (d) See also: Webb, M. R.; Donald,
C.; Taylor, R. J. K. Tetrahedron Lett. 2006, 47, 549.
(8) Connell, R. D.; Helquist, P.; Åkermark, B. J. Org. Chem.
1989, 54, 3359; this group also developed the phthalimide
variant of reagent 8..
We next demonstrated that the Boc group can be readily
removed (Scheme 4). Thus, treatment of N-Boc adduct 12
with TFA and anisole in dichloromethane produced the
corresponding pentadienylamine 24 in 90% yield. Due to
the highly unstable nature of this amine, it was immediate-
ly reprotected as the methyl carbamate derivative 25 for
characterisation purposes. The E,E/E,Z ratio was unal-
tered during these functional group transformations.
In summary, the easily prepared and crystalline Boc-pro-
tected PT-sulfone 11, when used in the Julia–Kocienski
olefination, provides a simple and convenient procedure
to convert a wide range of carbonyl compounds directly
into their corresponding Boc-protected pentadienyl
amines. The transformation proceeds in good to excellent
yields with KHMDS giving good levels of E-stereoselec-
tivity at the newly formed alkene (i.e., the 2E,4E-diene)
and LiHMDS generally giving a predominance of the
newly formed Z-alkene (i.e., the 2E,4Z-diene). We are
currently applying this methodology to prepare natural
products such as those shown in Figure 1.
(9) Baudin, J. B.; Hareau, B. G.; Julia, S. A.; Ruel, O.
Tetrahedron Lett. 1991, 32, 1175.
(10) (a) Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley,
A. Synlett 1998, 26. (b) Kocienski, P. J.; Bell, A.;
Blakemore, P. R. Synlett 2000, 365. (c) See also: Pospisil,
J.; Markó, I. E. Org. Lett. 2006, 8, 5983.
(11) For a review of the MJO, see: Blakemore, P. R. J. Chem.
Soc., Perkin Trans. 1 2002, 2563; and references therein.
(12) For recent applications in natural product synthesis, see:
(a) trans-Vaccenic acid: Duffy, P. E.; Quinn, S. M.; Roche,
H. M.; Evans, P. Tetrahedron 2006, 62, 4838. (b) [(–)-
Sagittamide A: Lievens, S. C.; Molinski, T. F. J. Am. Chem.
Soc. 2006, 128, 11764. (c) Piericidin A1 and B1:
Acknowledgment
We are grateful to the French Ministère des Affaires Etrangères for
a Lavoisier Fellowship and to the French Fondation Bettencourt-
Schuller for additional support (M.L.). We also thank the EPSRC
for PhD support (R.B., GR/T19971), and Heather Fish (University
of York) for her expert assistance with NMR spectroscopy.
Schnermann, M. J.; Romero, F. A.; Hwang, I.; Nakamaru-
Synlett 2008, No. 14, 2183–2187 © Thieme Stuttgart · New York

LETTER
Conversion of Carbonyl Compounds into Pentadienylamines
2187
Ogiso, E.; Yagi, T.; Boger, D. L. J. Am. Chem. Soc. 2006,
adducts. The reasons for this unexpected switch are not fully
understood at the present time but further studies are in
progress to shed light on this interesting observation.
(17) Preparation of 1-[N-(tert-Butoxycarbonyl)amino]-5-
phenylpenta-2,4-diene (12)
128, 11799. (d) Iejimalide B: Fürstner, A.; Aïssa, C.;
Chevrier, C.; Teply, F.; Nevado, C.; Tremblay, M. Angew.
Chem. Int. Ed. 2006, 45, 5832. (e) Cylindramide: Cramer,
N.; Buchweitz, M.; Laschat, S.; Frey, W.; Baro, A.; Mathieu,
D.; Richter, C.; Schwalbe, H. Chem. Eur. J. 2006, 12, 2488.
(f) Macrolide FD-891: Garcia-Fortanet, J.; Murga, M.;
Carda, J.; Marco, J. A.; Matesanz, R.; Diaz, J. F.; Barasoain,
I. Chem. Eur. J. 2007, 13, 5060.
To as stirred solution of PT-sulfone 11 (45 mg, 0.12 mmol,
1.2 equiv) in THF (1.4 mL) was added LiHMDS (0.26 mL
1.0 M in THF, 0.26 mmol, 2.55 equiv), or KHMDS (0.52
mL, 0.5 M in toluene, 0.26 mmol, 2.55 equiv), at –78 °C. In
the KHMDS case, 18-crown-6 (34 mg, 0.13 mmol, 1.2
equiv) was also present at the outset. After 1.5 h at the same
temperature, the orange mixture was added to benzaldehyde
(10.6 mg, 0.1 mmol, 1.0 equiv) in THF (0.9 mL) at –78 °C
via cannula. The mixture was stirred at –78 °C for 1.5 h and
then for 1 h at r.t. After quenching with brine (3 mL) and
stirring at r.t. for 10 min, the aqueous layer was extracted
with EtOAc (3 × 8 mL). The combined organic phases were
dried over MgSO4 and concentrated in vacuo. Purification
was performed via flash chromatography on SiO2 using
mixtures of PE and EtOAc as eluent to afford the product
alkenes as mixtures of their 2E,4E/2E,4Z isomers (ratio was
determined by 1H NMR spectroscopy).
(13) (a) Takano, D.; Nagamitsu, T.; Ui, H.; Shiomi, K.;
Yamaguchi, Y.; Masuma, R.; Kuwajima, I.; Omura, S. Org.
Lett. 2001, 3, 2289. (b) Schultz, H. S.; Freyermuth, H. B.;
Buc, S. R. J. Org. Chem. 1963, 28, 1140.
(14) Preparation of tert-Butyl (E)-4-(1-Phenyl-1H-tetrazol-5-
ylsulfonyl)but-2-enyl Carbamate (11)
To a solution of the sulfide 10 (7 g, 15.6 mmol) and Mo7O24
(NH4)6·4H2O (5.8 g, 4.7 mmol) in MeOH (130 mL) was
added 30% aq H2O2 (48.3 mL, 468 mmol) at r.t. The solution
was stirred for 1 h, and then sat. aq Na2S2O7 solution was
added to quench the excess of peroxide. After a stirring for
45 min at r.t., the reaction mixture was extracted with EtOAc
(3 × 100 mL), dried (NaSO4), and concentrated in vacuo;
purification by silica flash column chromatography (PE–
EtOAc, 1:1) gave the title sulfone 11 (5.6 g, 95%) as a white
solid, mp 86 °C; Rf = 0.56 (PE–EtOAc, 1:1). 1H NMR (400
MHz, CDCl3): d = 1.43 (s, 9 H, t-Bu), 3.77 (m, 2 H, CH2-1),
4.41 (d, J = 7.5 Hz, 2 H, CH2-4), 4.63 (br s, 1 H, NH), 5.29–
6.04 (m, 1 H, H-2), 6.00 (dt, J = 15.0, 7.5 Hz, 1 H, H-3),
7.57–7.60 (m, 5 H, Ar). 13C NMR (100 MHz, CDCl3): d =
28.7, 42.2, 59.5, 81.5, 114.5, 125.5, 130.0, 131.8, 133.3,
141.1, 153.4, 155.9. IR (neat): nmax = 3356, 2978, 1709,
1502, 1347, 1249, 1155 cm–1. HRMS: m/z calcd for
C16H21N5O4S [MH+]: 380.13925; found (CI): 380.1392 (0.1
ppm error).
Using KHMDS
72% (2E,4E/2E,4Z = 72:28); NMR data for major isomer
12E,E were comparable to those published.8
Using LiHMDS
72% (2E,4E/2E,4Z = 13:87) as a pale yellow solid, Rf = 0.71
(PE–EtOAc, 4:1); mp 42 °C. 1H NMR (400 MHz, CDCl3;
major isomer): d = 1.43 (s, 9 H, t-Bu), 3.81 (m, 2 H, H-1),
4.58 (br s, 1 H, NH), 5.84 (dt, 1 H, J = 15.0, 5.5 Hz, H-2),
6.23 (t, 1 H, J = 11.6 Hz, H-4), 6.23 (t, 1 H, J = 11.5 Hz,
H-4), 6.42 (d, 1 H, J = 11.5 Hz, H-5), 6.69 (dddd, J = 15.0,
11.5, 2.5, 1.5 Hz, 1 H, H-3), 7.36–7.25 (m, 5 H, Ar). 13
C
NMR (100 MHz, CDCl3; major isomer): d = 28.1, 42.2,
81.5, 127.9, 128.5, 128.7, 129.4, 129.6, 130.9, 132.9, 137.6,
156.1. IR (neat): nmax = 3318, 2978, 1677, 1531, 1365, 1275,
1166, 995 cm–1. HRMS: m/z calcd for C16H21NNaO2
[MNa]+: 282.1470; found: 282.1465 (3.5 ppm error)].
(18) All novel compounds were fully characterised (sometimes
as E,E/E,Z mixtures) including confirmation by high-field
NMR and HRMS.
(15) Hilpert, H.; Wirz, B. Tetrahedron 2001, 57, 681.
(16) The Julia–Kocienski olefination is normally trans-selective
due to the kinetically controlled and irreversible addition of
metallated PT-sulfones to aldehydes preferentially
generating anti-b-alkoxysulfones, which then undergo
Smile rearrangement.10,11 In the present study, it would
appear that LiHMDS preferentially generates syn-b-
alkoxysulfones resulting in a predominance of the E,Z-
Synlett 2008, No. 14, 2183–2187 © Thieme Stuttgart · New York

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