Carbon-carbon bond formation via a tandem cationic 2-aza-Cope rearrangement-Lewis acid promoted Petasis reaction

Article abstract of DOI:10.1016/j.tet.2008.02.025

Potassium alkynyltrifluoroborates and potassium (2-phenyl)vinyltrifluoroborates react with N-3-butenyl-(2,2-dichloro-1-propylidene)amine in the presence of BF₃·Et₂O as a Lewis acid to synthesize rearranged Mannich products. The reaction starts with a cationic 2-aza-Cope rearrangement of the imine, followed by the Lewis acid promoted borono-Mannich-type reaction on the rearranged imine to result in a new class of functionalized N-homoallylamines.

Full text of DOI:10.1016/j.tet.2008.02.025

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3457e3463
www.elsevier.com/locate/tet
Carbonecarbon bond formation via a tandem cationic 2-aza-Cope
rearrangementeLewis acid promoted Petasis reaction
*
Sara Stas, Kourosch Abbaspour Tehrani , Georges Laus
Faculty of Sciences, Department of Applied Biological Sciences and Engineering, Laboratory for Organic Chemistry,
Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium
Received 11 January 2008; received in revised form 7 February 2008; accepted 7 February 2008
Available online 9 February 2008
Abstract
Potassium alkynyltrifluoroborates and potassium (2-phenyl)vinyltrifluoroborates react with N-3-butenyl-(2,2-dichloro-1-propylidene)amine
in the presence of BF3$Et2O as a Lewis acid to synthesize rearranged Mannich products. The reaction starts with a cationic 2-aza-Cope rear-
rangement of the imine, followed by the Lewis acid promoted borono-Mannich-type reaction on the rearranged imine to result in a new class of
functionalized N-homoallylamines.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Boron; Imine; 2-Aza-Cope; Tandem reaction; Petasis
1. Introduction
The most attractive feature of this rearrangement is the re-
organization occurring under remarkably mild conditions, typ-
ically at rt. The main drawback of the method is the
reversibility of the process. To be synthetically useful, the cat-
ionic 2-aza-Cope rearrangement should be irreversible in a cer-
tain direction. Therefore, many applications are carried out in
benzo-heterocyclic systems where the rearrangement is driven
by aryl conjugation of the product iminium ion (R3¼aryl in
Scheme 1).3 Another strategy to direct the rearrangement is
to combine the cationic aza-Cope rearrangement with a subse-
quent reaction, which drives this equilibrated sigmatropic pro-
cess towards a final product.4 Three different tandem reactions
have been described in the literature with the cationic aza-
Cope process as the first reaction taking place. The second
step can be an iminium ion hydrolysis in which one of the imi-
nium isomers is more reactive to water than the more
substituted iminium group.4,5 In some isolated examples this
has been effected via an iminium ion reduction.6 A nucleo-
phile induced eneeiminium cyclization is another possibility
to drive the equilibrium towards the desired product.7 The
most intensively documented tandem process is the aza-
CopeeMannich cyclization.8 This last tandem process, first
introduced by Overman, is only possible with iminium salts
containing a 2-oxygenated homoallylamine moiety. This
The aza-Cope rearrangement is a well known synthetic
route for the formation of new carbonecarbon bonds under
mild reaction conditions.1e11 Depending on the nitrogen-posi-
tion (n) in the substrate, the rearrangement is identified as
n-aza-Cope rearrangement. 3-Aza-Cope rearrangements have
been extensively described in literature and occur within
N-allylic enamines with a geminally disubstituted enamine
system.1 The 2-aza-Cope rearrangement has been mainly
reported as taking place with iminium salts and, in that case,
it is referred to as cationic 2-aza-Cope or azonia-[3,3]-sigma-
tropic rearrangement (Scheme 1).2e11
R2
N
R2
N
R3
R4
R1
R6
R3
R4
R1
R6
R5
R5
1
2
Scheme 1. Reversible cationic aza-Cope rearrangement.
* Corresponding author. Tel.: þ32 (0)26293292; fax: þ32 (0)26293304.
E-mail address: kourosch.abbaspour.tehrani@vub.ac.be (K. Abbaspour
Tehrani).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.025

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S. Stas et al. / Tetrahedron 64 (2008) 3457e3463
method allows a variety of polysubstituted pyrrolidines like
3-acylpyrrolidines 5 to be obtained in excellent yields from
aldehydes 3 and 2-oxygenated homoallylic amines 4 (Scheme
2). The tandem aza-Cope rearrangementeMannich reaction
was employed as the key step in the total synthesis of several
complex natural products like tricyclic amines9 and different
alkaloids10 such as asparagamine A,10a strychnine,10b pancra-
cine,10c melsocine,8c Amaryllidaceae alkaloids10d and many
others.11
product and side products (phenylacetylene or styrene) could
be obtained from the crude reaction mixtures by preparative
1
HPLC. H NMR-analysis of the products indicated the ab-
sence of a typical singlet or a doublet in the 3.4e4 ppm region,
and suggested the formation of other compounds than the ex-
pected Mannich bases 9 or 11. Complete spectral investigation
of these compounds by means of both 1-D (1H NMR, 13C
NMR) and 2-D (HMBC and HMQC) allowed us to assign
the structures of the rearranged homoallylamines 10 and 12
to the above obtained Mannich products. Because of the rather
low yields of the homoallylamines 10 (31%) and 12 (16%), an
alternate purification by flash chromatography (silica gel) was
attempted. This, however, resulted in even lower isolated
yields of 25% for 10 and 11% for 12.14
O
R4
R4
H2
N
benzene
reflux 5 h
R1CHO
+
R2
X
R1
OR3
N
R2
3
4
5
These results are in accordance with a tandem cationic
aza-Cope rearrangementeLewis acid promoted Mannich pro-
cess as reaction mechanism. In order to confirm this reaction
mechanism, deuterium labelled N-3-butenyl-(2,2-dichloro-
1-propylidene)amine (16) was synthesized. First 1,1-
dideuteriobut-3-enylamine (14) was prepared by reduction
of allylcyanide (13) with trideuterioalane.13a The rather low
isolated yield of 19% can be explained by the high water sol-
ubility of 14. In a next step, 14 was used in reaction with
2,2-dichloropropanal (15) to prepare the corresponding deu-
terated imine 16 with a yield of 37%. It was gratifying to ob-
serve that the reaction of the dideuterated imine 16 with
potassium phenylethynyltrifluoroborate (7) or potassium (2-
phenyl)vinyltrifluoroborate in the presence of BF3$Et2O
led, respectively, to the dideuterated rearranged Mannich
Scheme 2. Tandem aza-Cope rearrangementeMannich cyclization.
To the best of our knowledge, tandem aza-CopeeMannich
reactions were only described to create aza-heterocycles, but
were never used to synthesize acyclic amines.
Recently we developed a new modified Petasis reaction
with a,a-dichlorinated aldimines as carbonyl equivalents,
and organodifluoroboranes, synthesized in situ from organotri-
fluoroborates and BF3$Et2O, as nucleophilic compounds.12
Despite the extensive use of tandem cationic aza-Cope rear-
rangementseMannich reaction, there have been no reports us-
ing a (modified) Petasis reaction as second step. In the present
paper, we describe the extension of this Lewis acid promoted
Mannich-type reaction to the use of N-3-butenyl-(2,
2-dichloro-1-propylidene)amine as the imine-component.
1
products 17 and 18. H NMR spectral analysis clearly re-
vealed the position of both deuterium atoms on the methy-
lene carbon next to the nitrogen atom (Scheme 4).
2. Results and discussion
Scheme 5 shows the mechanistic details of this tandem
aza-Cope rearrangementemodified Petasis reaction. In the
three-component reaction mixture of deuterated imine 16, or-
ganotrifluoroborate and BF3$Et2O, first the formation of the
very electrophilic difluoroborane15,12 takes place, which coor-
dinates with the imine to form iminium species 19. Next, a cat-
ionic 2-aza-Cope rearrangement of the iminium salt, similar to
the aza-Cope rearrangements described in literature,2 occurs
N-3-Butenyl-(2,2-dichloro-1-propylidene)amine (6) was
synthesized in 66% yield by stirring 2,2-dichloropropanal
and 3-butenylamine13 in CH2Cl2 in the presence of anhydrous
MgSO4 as desiccant. Imine 6 was subsequently used without
any further purification in a one-pot Mannich reaction
(Scheme 3) with potassium phenylethynyltrifluoroborate (7)
or potassium (2-phenyl)vinyltrifluoroborate (8), in the pres-
ence of BF3$Et2O. Unreacted starting material, reaction
1 equiv
BF3K
7
Cl Cl
Cl Cl
Cl Cl
HN
H
1 equiv BF3.Et2O
X
CH2Cl2
HN
N
rt, 18 h
9
6
10 (31%)
1 equiv
BF3K
8
Cl Cl
HN
Cl Cl
Cl Cl
H
1 equiv BF3.Et2O
X
CH2Cl2/HFIP (9/1)
HN
N
rt, 18 h
11
6
12 (16%)
Scheme 3. Lewis acid promoted Mannich-type reaction with N-3-butenyl-(2,2-dichloro-1-propylidene)amine results in rearranged Mannich products.

S. Stas et al. / Tetrahedron 64 (2008) 3457e3463
Table 1
3459
Cl Cl
Cationic aza-Copeemodified Petasis reaction with arylethynyltrifluoroborates
1 equiv
R
HN
D
D
iii
BF3K
R
17
Cl Cl
Cl Cl
24
H
1 equiv
Cl Cl
1 equiv BF3.Et2O
CH2Cl2, rt, 18 h
HN
N
H
6
25
Cl Cl
D
D
15
O
H
i
CN
NH2
R (24)
H (7)
3-OMe (24a)
Yield 25a (%)
ii
N
13
14
16
31 (10)
27 (25a)
17 (25b)
D
D
iv
4-Et (24b)
a
Yield after preparative HPLC.
Cl Cl
HN
amine (6), potassium arylethynyltrifluoroborates 24 with
electron-donating substituents and BF3$Et2O also resulted in
moderate isolated yields of the rearranged Mannich products
25 (Table 1).
D
D
18
Scheme 4. Deuterium labelling strategy. Reagents and conditions: (i) AlCl3
(1 equiv), LiAlD4 (1 equiv), Et2O, 0 ꢀC, 1.5 h (19%); (ii) anhydrous MgSO4
(3 equiv), CH2Cl2, reflux, 2 h (37%); (iii) 7 (1 equiv), BF3$Et2O (1 equiv),
CH2Cl2, rt, 18 h (17%); (iv) 8 (1 equiv), BF3$Et2O (1 equiv), CH2Cl2/HFIP
(9/1), rt, 18 h (7%).
The sigmatropic rearrangementeMannich reaction tandem
process was also evaluated with aliphatic alkynyltrifluorobo-
rates like potassium (3-methoxy-1-propynyl)trifluoroborate
(Scheme 6). During flash chromatography of the reaction mix-
ture two products were isolated. Besides the expected rear-
ranged Mannich product 26 (13% yield) also a minor side
product was obtained, which could be identified as a tertiary
amine 29 with two 4-methoxy-2-butynyl nitrogen substituents
(2% yield). It is assumed that this side product is formed by an
addition of the rearranged Mannich product 26 to the least
sterical hindered sigmatropic isomer 27, formed during the
cationic 2-aza-Cope rearrangement. Intramolecular transfer
of the 3-methoxypropargyl group in the intermediate aminal
28 to the aminal-carbon finally results in the tertiary amine
29. The side product 30, formed according to the proposed
mechanism, has never been observed, probably because of
its volatility. The reason why this extra product is formed
here, and not in the other aza-CopeeMannich reactions,
remains unclear.
through a cyclic transition state 20, giving rise to a new imi-
nium ion 21, which is less sterically hindered than the starting
sigmatropic isomer 19. Therefore a Mannich reaction prefera-
bly takes place with 21 as imine-component: the R-group is
transferred to the electrophilic deuteriomethylene group and
after aqueous work-up the intermediate aminodifluoroborane12
22 is converted to the rearranged Mannich product 23. In the
literature the equilibrium is shifted to the sigmatropic isomer,
which experiences either aryl conjugation3 with an arylgroup
in a-position of the iminium ion or mesomeric stabilization8
in the presence of an allylic alkoxy group. The rather low
yields, observed in our reaction, may be explained by the ab-
sence of any of these stabilizing factors. The only driving
force here being the final Lewis acid modified Petasis reaction
on less sterically hindered iminium isomer 21. In this context
it is worth mentioning that no trace of the product of a modified
Petasis reaction was ever observed from starting imine 16.
This process is the first example of a tandem aza-Copee
borono-Mannich reaction leading to aliphatic amines.
3. Conclusion
Since the yield obtained in the tandem process with potas-
sium (2-phenyl)vinyltrifluoroborate is lower compared to
potassium phenylethynyltrifluoroborate, and because the
previously reported Lewis acid promoted Mannich-type reac-
tion12 also resulted in better yields when alkynyltri-
fluoroborates were used, the scope of this reaction with regard
to different alkynyltrifluoroborates was investigated. The
reaction between N-3-butenyl-(2,2-dichloro-1-propylidene)-
In summary, a tandem cationic 2-aza-Cope rearrangemente
Lewis acid promoted borono-Mannich reaction of N-3-bu-
tenyl-(2,2-dichloro-1-propylidene)amine with organotrifluoro-
borates was developed. This hitherto unreported type of
aza-Cope rearrangement in combination with a modified
Petasis reaction provides a new route to a new class of gemi-
nally dichlorinated secondary homoallylamines. This novel
variation of the modified Petasis reaction occurs through
Cl Cl
Cl Cl
Cl Cl
RBF3K
BF3.Et2O
Cl Cl
Cl Cl
Cl Cl
aqueous
workup
H
N
N
N
N
D
N
R
HN
R
F
F
B
R
F2B
R
F
F
B
R
F2B
D
D
D
D
D
D
D
D
D D
D
16
19
20
21
22
23
Scheme 5. Reaction mechanism of the tandem cationic 2-aza-Cope rearrangementeLewis acid promoted borono-Mannich reaction.

3460
S. Stas et al. / Tetrahedron 64 (2008) 3457e3463
Cl Cl
N
29 (2%)
OMe
R
N
R
H
B
Cl Cl
F
Cl Cl
HN
N
MeO
F
+
+
N
OMe
F
B
F
Cl Cl
27
26 (13%)
28
MeO
OMe
HN
MeO
BF2
Cl Cl
30
with R =
Scheme 6. Tandem 2-aza-Cope rearrangementeLewis acid promoted Mannich reaction with potassium (3-methoxy-1-propynyl)trifluoroborate.
a tandem process in which first a 2-azonia-[3,3]-sigmatropic
rearrangement of the iminium salt, formed between imine
and organodifluoroborane, takes place, followed by the Lewis
acid promoted Mannich reaction.
ORGANICS for a generous gift of 3-butenylamine (purity of
90% in NMR).
4.1.1. Synthesis of 1,1-dideuteriobut-3-enylamine (14)
This compound was prepared analogous to the procedure
for the preparation of 3-butenylamine.13a
Yield: 832 mg (scale 60 mmol, yield 19%), colourless
liquid.
4. Experimental
4.1. General
1H NMR (250 MHz, CDCl3): d 5.81e5.73 (1H, m,
CH2CH]CH2), 5.15e5.05 (2H, m, CH2CH]CH2), 2.19 (2H,
d, J¼6.2 Hz, CD2CH2).
GCeMS analyses were performed using an Interscience,
GC 8000 series gas chromatograph with an ECÔ-5 column
(length: 30 m, internal diameter: 0.32 mm, film thickness:
0.25 mm). Products are injected in a split injector (250 ꢀC);
the inert carrier gas is helium. The mass spectrometer is a
Fisons Instruments MD 800 using electron impact (70 eV)
as ionization method. HRMS was measured with a VGQuattro
13C NMR (62.90 MHz, CDCl3): d 136.2 (CH2CH]CH2),
116.6 (CH2CH]CH2), 40.5 (CD2, quintet, J¼21.1 Hz), 37.9
(CD2CH2).
IR (ATR, cmꢁ1): nmax 3074, 2924, 2843, 2610, 1619, 1391,
1367, 1004, 975, 829, 700, 661.
1
II mass spectrometer. High resolution H NMR (250 MHz)
and 13C NMR (62.9 MHz) spectra were recorded in CDCl3
on a Bruker Avance DRX 250 spectrometer. Chemical shifts
are reported in parts per million downfield from TMS. 13C
NMR assignments were made using DEPT, HMQC and
HMBC spectra. Infrared spectra were recorded with an Avatar
370 FT-IR apparatus (Thermo Nicolet). Unless otherwise
stated, the IR-spectra were recorded using the attenuated total
reflection technology. Flash chromatography was performed
using Merck silica (diameter 40e63 mm). TLC-analysis was
performed on glass backed plates (Merck) coated with
0.2 mm silica with UV-indicator 60F254. Preparative HPLC
was performed using a Gilson HPLC (332 PUMP) and a Gilson
UV-detector (UV/VIS-156) with a reversed phase Discovery
BIO wide pore C18 column (length: 25 cm, internal diameter:
21.2 mm, particle size: 10 mm) using a MeCN/H2O gradient
containing 0.1% TFA. Potassium (2-phenylvinyl)trifluorobora-
te,16a potassium phenylethynyltrifluoroborate,16b potassium
(3-methoxyphenyl)ethynyltrifluoroborate,12 potassium (4-eth-
ylphenyl)ethynyltrifluoroborate12 and potassium (3-methoxy-
1-propynyl)trifluoroborate16c were prepared according to
literature procedures. 2,2-Dichloropropanal was prepared by
halogenation of propanal with chlorine gas.17 Deuterated and
non-deuterated 3-butenylamine were synthesized according
to literature procedures.13a,b We are also grateful to EBURON
4.2. Synthesis of N-3-butenyl-(2,2-dichloro-1-propylidene)-
amine (6); general procedure
To
a stirred solution of 2,2-dichloropropanal (15)
(50 mmol, 6.35 g) in CH2Cl2 (50 mL) was added
MgSO4$3H2O (150 mmol, 26.16 g) as desiccant, followed
by 3-butenylamine (47.5 mmol, 3.38 g). The solution was
stirred under reflux for 2 h. Afterwards, the solution was fil-
tered and concentrated under reduced pressure. Yield: 5.91 g
(66%), colourless liquid.
1H NMR (250 MHz, CDCl3): d 7.76 (1H, s, HCN), 5.85e
5.69 (1H, m, CH2CH]CH2), 5.17e5.03 (2H, m, CH2CH]
CH2), 3.57 (2H, t, J¼6.9 Hz, NCH2), 2.39 (2H, q, J¼6.9 Hz,
CH2CH]CH2), 2.26 (3H, s, CH3).
13C NMR (62.90 MHz, CDCl3): d 160.6 (CN), 135.3
(CH2CH]CH2), 116.8 (CH2CH]CH2), 84.5 (CCl2), 58.6
(NCH2), 34.1 (CH2CH]CH2), 32.6 (CH3).
IR (ATR, cmꢁ1): n 1667 (C]N), 1437, 1380 (HC]CH2).
MS (70 eV, m/z (%)): 183 ([Mþ4]þ, 0.6), 181 ([Mþ2]þ, 1.6),
179 (Mþ, 1.3), 140 (52), 138 (58), 111 (17), 110 (15), 109 (15),
105 (14), 104 (16), 102 (50), 97 (19), 82 (83), 79 (19), 78 (18),
76 (72), 68 (28), 67 (25), 63 (16), 61 (29), 54 (100), 51 (38).

S. Stas et al. / Tetrahedron 64 (2008) 3457e3463
3461
4.2.1. N-(2,2-Dichloro-1-propylidene)-(1,1-dideuterio-3-
butenyl)amine (16)
1H NMR (250 MHz, CDCl3): d 7.39e7.19 (5H, m, aro-
mate), 6.50 (1H, d, J¼15.9 Hz, CHCHCarom.quat.), 6.22 (1H,
dꢂt, J¼15.9, 6.4 Hz, CHCHCarom.quat.), 5.99e5.82 (1H, m,
CH2CH]CH2), 5.22e5.15 (2H, m, CH2CH]CH2), 3.56
(2H, dꢂd, J¼6.4, 1.3 Hz, NHCH2), 2.98e2.93 (1H, m,
CHNH), 2.90e2.85 and 2.32e2.23 (2ꢂ1H, 2ꢂm,
CH2CH]CH2), 2.19 (3H, s, CH3).
13C NMR (62.90 MHz, CDCl3): d 136.9 (Carom.quat.), 135.3
(CHCHCarom.quat.), 131.5 (CHCHCarom.quat.), 128.6 (Carom.ortho),
128.2 (CH2CH]CH2), 127.5 (Carom.para), 126.3 (Carom.meta),
118.0 (CH2CH]CH2), 95.3 (CCl2), 68.5 (CHNH), 52.2
(NHCH2), 37.2 (CH2CH]CH2), 34.5 (CH3).
IR (ATR, cmꢁ1): n 1494, 1447 (C]C aromate), 1370
(HC]CH).
Compound 16 was prepared in an analogous manner.
Yield: 670 mg (scale 10 mmol, yield 37%), light-yellow oil.
1H NMR (250 MHz, CDCl3): d 7.76 (1H, s, HCN), 5.79e
5.69 (1H, m, CH2CH]CH2), 5.13e5.03 (2H, m, CH2CH]
CH2), 2.51 (2H, d, J¼6.8 Hz, CH2CH]CH2), 2.27 (3H, s, CH3).
13C NMR (62.90 MHz, CDCl3): d 159.8 (CN), 134.5
(CH2CH]CH2), 118.4 (CH2CH]CH2), 83.7 (CCl2), 31.8
(CH2CH]CH2), 30.6 (CH3), quintet of CD2 is not visible.
IR (ATR, cmꢁ1): n 1641, 1620 (C]N), 1378, 1353 (C]C).
MS (70 eV, m/z (%)): 185 ([Mþ4]þ, 3), 183 ([Mþ2]þ, 9),
181 (Mþ, 11), 146 (99), 140 (98), 109 (98), 103 (100), 99
(51), 97 (54), 83 (99), 75 (99), 68 (100), 61 (99), 52 (99).
MS (70 eV, m/z (%)): 287 ([Mþ4]þ, trace), 285 ([Mþ2]þ,
trace), 283 (Mþ, trace), 214 (11), 213 (80), 132 (11), 118 (9),
117 (100), 115 (78), 108 (9), 102 (8), 94 (18), 91 (44), 89 (9),
77 (13), 65 (12), 63 (8), 53 (17), 51 (13).
4.3. Synthesis of the dichlorinated homoallylamines; general
procedure
To a stirred solution of 6 (0.5 mmol, 89 mg) in CH2Cl2
(4 mL) was added the potassium alkynyltrifluoroborate
(1 equiv, 0.5 mmol) in one portion, followed by BF3$Et2O
(1 equiv, 0.5 mmol, 71 mg). The reaction mixture was stirred
for 18 h at rt and poured into aqueous NaOH (4 mL, 0.5 M).
After isolation of the organic layer, the aqueous phase was
washed with CH2Cl2 (4ꢂ5 mL). The organic fractions were
dried (MgSO4) and concentrated under reduced pressure.
The reaction with potassium (2-phenylvinyl)trifluorobo-
rates was carried out in the same way but with CH2Cl2/HFIP
(9/1) as solvent mixture. Unless otherwise stated, all these
reactions were purified by preparative HPLC.
HRMS (ESI): m/z calcd for C15H19NCl2þH: 284.0973;
found: 284.0894.
4.3.3. N-(5,5-Dichloro-1-hexene-4-yl)-(1,1-dideuterio-3-
phenyl-2-propynyl)amine (17)
Yield: 24 mg (17%), yellow oil.
1H NMR (250 MHz, CDCl3): d 7.38e7.31 (2H, m,
CHarom.ortho), 7.26e7.21 (3H, m, CHarom.metaþpara), 5.99e5.82
(1H, m, CH2CH]CH2), 5.17e5.06 (2H, m, CH2CH]CH2),
3.13 (1H, dꢂd, J¼9.4, 3.2 Hz, CHNH), 2.89e2.79 and
2.23e2.15 (2ꢂ1H, 2ꢂm, CH2CH]CH2), 2.12 (3H, s, CH3).
13C NMR (62.90 MHz, CDCl3): d 134.1 (CH2CH]CH2),
130.5 (Carom.ortho), 127.3 (Carom.meta), 127.1 (Carom.para),
122.0 (Carom.quat.), 117.3 (CH2CH]CH2), 94.0 (CCl2), 86.4
(C^CCarom.quat.), 82.8 (C^CCarom.quat.), 66.6 (CHNH),
38.3e37.2 (CD2, m), 35.9 (CH2CH]CH2), 33.1 (CH3).
IR (ATR, cmꢁ1): n 3356 (NH), 2079 (C^C), 1640, 1598,
1489, 1442 (C]C aromate), 1372, 1337, 1269 (HC]CH,
CH]CH2).
4.3.1. N-(5,5-Dichloro-1-hexene-4-yl)-(3-phenyl-2-propynyl)-
amine (10)
Yield: 44 mg (31%), dark-yellow oil.
1H NMR (250 MHz, CDCl3): d 7.47e7.38 (2H, m,
CHarom.ortho), 7.33e7.25 (3H, m, CHarom.metaþpara),
6.06e5.89 (1H, m, CH2CH]CH2), 5.25e5.13 (2H, m,
CH2CH]CH2), 3.83 (2H, s, NHCH2), 3.21 (1H, dꢂd,
J¼9.3, 3.2 Hz, CHNH), 2.97e2.86 and 2.31e2.22 (2ꢂ1H,
2ꢂm, CH2CH]CH2), 2.20 (3H, s, CH3).
MS (70 eV, m/z (%)): 283 (Mþ, 0.2), 279 (Mþꢁ(2ꢂD),
0.4), 186 (100), 176 (37), 175 (39), 155 (65), 153 (37), 145
(36), 141 (51), 139 (53), 128 (36), 117 (35), 115 (86), 114
(63), 99 (62), 97 (87), 77 (35), 63 (46), 61 (40), 57 (60).
HRMS (ESI): m/z calcd for C15H15D2NCl2þH: 284.0932;
found: 284.0901.
13C NMR (62.90 MHz, CDCl3): d 135.1 (CH2CH]CH2),
131.5 (Carom.ortho), 128.3 (Carom.meta), 128.1 (Carom.para),
123.0 (Carom.quat.), 118.4 (CH2CH]CH2), 94.9 (CCl2), 87.4,
83.9 (C^CCarom.), 67.7 (CHNH), 39.5 (NHCH2), 36.9
(CH2CH]CH2), 34.2 (CH3).
4.3.4. N-(5,5-Dichloro-1-hexene-4-yl)-(1,1-dideuterio-
3-phenyl-2-propenyl)amine (18)
IR (ATR, cmꢁ1): n 3363 (NH), 1640, 1598 (C]C aromate),
1489, 1441 (HC]CH).
Yield: 10 mg (7%), yellow oil.
MS (70 eV, m/z (%)): 285 ([Mþ4]þ, 0.4), 283 ([Mþ2]þ, 2),
281 (Mþ, 3), 242 (36), 240 (37), 204 (13), 185 (21), 184 (50),
167 (12), 115 (100), 113 (10), 102 (16), 89 (31), 82 (11), 77
(13), 65 (16), 63 (21).
1H NMR (250 MHz, CDCl3): d 7.32e7.13 (5H, m, aro-
mate), 6.44 (1H, d, J¼15.9 Hz, CHCHCarom.quat.), 6.15 (1H,
d, J¼15.9 Hz, CHCHCarom.quat.), 5.92e5.76 (1H, m,
CH2CH]CH2), 5.17e5.08 (2H, m, CH2CH]CH2), 2.94e
2.84 (1H, m, CHNH), 2.83e2.78 and 2.28e2.17 (2ꢂ1H,
2ꢂm, CH2CH]CH2), 2.13 (3H, s, CH3).
HRMS (ESI): m/z calcd for C15H17NCl2þH: 282.0816;
found: 282.0843.
13C NMR (62.90 MHz, CDCl3): d 135.8 (Carom.quat.), 134.1
(CH2CH]CH2), 131.5e130.8 (CHCHCarom.quat., m due to
4.3.2. N-(5,5-Dichloro-1-hexene-4-yl)-(3-phenyl-2-propenyl)-
amine (12)
Yield: 23 mg (16%), dark-yellow oil.
coupling with D), 127.6 (Carom.meta), 126.6 (Carom.para
CHCHCarom.quat.), 125.3 (Carom.ortho), 117.2 (CH2CH]CH2),
þ

3462
S. Stas et al. / Tetrahedron 64 (2008) 3457e3463
93.8 (CCl2), 67.4 (CHNH), 50.5e50.1 (CD2, m), 35.9
(CH2CH]CH2), 33.4 (CH3).
IR (ATR, cmꢁ1): n 1491, 1452, 1413 (C]C aromate), 1258
(HC]CH, CH]CH2).
(CH2CH]CH2), 33.2 (CH3CCl2), 27.7 (CH2CH3), 14.3
(CH2CH3).
IR (ATR, cmꢁ1): n 3356 (NH), 1509, 1437 (C]C aromate),
1372, 1329 (HC]CH2).
MS (70 eV, m/z (%)): 281 (Mþꢁ(2ꢂD), 1), 218 (31), 216
(96), 214 (100), 178 (45), 106 (39), 99 (40), 97 (54), 89
(38), 80 (38), 79 (57), 77 (50), 75 (38), 65 (40), 63 (49), 61
(49), 54 (38), 51 (40).
MS (70 eV, m/z (%)): 313 ([Mþ4]þ, 0.1), 311 ([Mþ2]þ,
0.6), 309 (Mþ, 1), 270 (10), 268 (15), 213 (10), 212 (55),
144 (32), 143 (100), 141 (15), 129 (9), 128 (60), 127 (18),
115 (27), 102 (9), 99 (6), 91 (5), 89 (5), 77 (7), 65 (5), 63 (8).
HRMS (ESI): m/z calcd for C17H21NCl2þH: 310.1129;
found: 310.1086.
HRMS (ESI): m/z calcd for C15H17D2NCl2þH: 286.1088;
found: 286.1037.
4.3.5. N-(5,5-Dichloro-1-hexene-4-yl)-[3-(3-methoxyphenyl)-
2-propynyl]amine (25a)
Yield: 42 mg (27%), yellow oil.
4.3.7. N-(5,5-Dichloro-1-hexene-4-yl)-(4-methoxy-2-
butynyl)amine (26)
Yield: 16 mg (13% after flash chromatography with
CH2Cl2/EtOH (99/1), Rf¼0.25), light-yellow oil.
1H NMR (250 MHz, CDCl3): d 6.01e5.84 (1H, m,
CH2CH]CH2), 5.22e5.14 (2H, m, CH2CH]CH2), 4.11
(2H, t, J¼1.9 Hz, CH2OMe), 3.65 (2H, t, J¼1.9 Hz,
NHCH2), 3.38 (3H, s, OMe), 3.10 (1H, dꢂd, J¼9.3, 3.2 Hz,
CHCCl2), 2.93e2.82 and 2.27e2.20 (2ꢂ1H, 2ꢂm,
CH2CH]CH2), 2.16 (3H, s, CCl2CH3).
13C NMR (62.90 MHz, CDCl3): d 134.0 (CH2CH]CH2),
117.3 (CH2CH]CH2), 93.9 (CCl2), 83.5 (C^CCH2OMe),
78.4 (C^CCH2OMe), 66.7 (CHCCl2), 59.0 (NHCH2), 56.6
(OMe), 37.9 (CH2OMe), 35.9 (CH3CCl2), 33.1 (CH2CH]
CH2).
IR (ATR, cmꢁ1): n 3657 (NH), 1641 (C^C), 1376, 1356
(HC]CH2).
MS (70 eV, m/z (%)): 254 ([Mþ5]þ, 0.1), 252 ([Mþ3]þ,
0.3), 250 ([Mþ1]þ, 0.5), 210 (83), 208 (92), 172 (21), 153
(25), 152 (100), 107 (27), 106 (28), 104 (20), 94 (22), 93
(24), 92 (26), 91 (54), 80 (41), 79 (28), 77 (72), 70 (21), 68
(50), 65 (23), 55 (54), 53 (74), 52 (36), 51 (32).
HRMS (ESI): m/z calcd for C11H17NOCl2þH: 250.0765;
found: 250.0885.
1H NMR (250 MHz, CDCl3): d 7.15 (1H, dꢂd, J¼7.9,
7.9 Hz,
Carom.quat.CHarom.CHarom.CHarom.Carom.quat.), 6.94
(1H, dꢂdꢂd, J¼7.6, 1.1, 1.1 Hz, C^CCarom.quat.CHarom.),
6.88 (1H, dꢂdzt, J¼1.8 Hz, Carom.quat.CHarom.Carom.quat.),
6.80 (1H, dꢂdꢂd, J¼8.2, 2.4, 1.0 Hz, CHarom.Carom.quat.OMe),
5.99e5.82 (1H, m, CH2CH]CH2), 5.17e5.07 (2H, m,
CH2CH]CH2), 3.74 (2H, s, NHCH2), 3.73 (3H, s, OMe),
3.12 (1H, dꢂd, J¼9.4, 3.2 Hz, CHCCl2), 2.89e2.79 and
2.23e2.16 (2ꢂ1H, 2ꢂm, CH2CH]CH2), 2.12 (3H, s, CH3),
1.55 (1H, s, NH).
13C NMR (62.90 MHz, CDCl3): d 159.3 (Carom.quat.OMe),
134.1 (CH2CH]CH2), 128.4 (MeOCarom.quat.CHarom.CHarom.),
123.0 (C^CCarom.quat.), 123.0 (C^CCarom.quat.CHarom.), 117.3
(CH2CH]CH2), 115.5 (MeOCarom.quat.CHarom.), 113.6
(Carom.quat.CHarom.Carom.quat.), 94.0 (CCl2), 86.3 (C^C-
Carom.quat.), 82.7 (C^CCarom.quat.), 66.7 (CHNH), 54.2
(MeO), 38.5 (NHCH2), 36.0 (CH2CH]CH2), 33.1 (CH3CCl2).
IR (ATR, cmꢁ1): n 3361 (NH), 1575, 1597 (C]C aromate),
1488, 1480, 1464, 1430 (HC]CH2).
MS (70 eV, m/z (%)): 315 ([Mþ4]þ, trace), 313 ([Mþ2]þ,
0.2), 311 (Mþ, 0.2), 214 (11), 146 (10), 145 (100), 130 (15),
115 (31), 102 (50), 99 (12), 97 (18), 91 (14), 89 (18), 77 (14),
76 (17), 75 (14), 65 (11), 63 (33), 62 (11), 61 (12), 54 (16), 53
(14), 51 (11).
4.3.8. N-(5,5-Dichloro-1-hexene-4-yl)[bis(4-methoxy-2-
butynyl)]amine (29)
HRMS (ESI): m/z calcd for C16H19NOCl2þH: 312.0922;
found: 312.0886.
Yield: 4 mg (2% after flash chromatography with CH2Cl2/
EtOH (99/1), Rf¼0.32), yellow oil.
4.3.6. N-(5,5-Dichloro-1-hexene-4-yl)-[3-(4-ethylphenyl)-2-
propynyl]amine (25b)
1H NMR (250 MHz, CDCl3): d 6.05e5.89 (1H, m,
CH2CH]CH2), 5.30e5.05 (2H, m, CH2CH]CH2), 4.11
(2ꢂ2H, t, J¼1.8 Hz, 2ꢂCH2OMe), 3.80 (2H, t, J¼1.8 Hz,
NHCH2), 3.78 (2H, t, J¼1.8 Hz, NHCH2), 3.45 (1H, dꢂd,
J¼9.6, 3.4 Hz, CHCCl2), 3.38 (2ꢂ3H, s, 2ꢂOMe), 2.94e
2.83 and 2.73e2.60 (2ꢂ1H, 2ꢂm, CH2CH]CH2), 2.21 (3H,
s, CCl2CH3).
Yield: 27 mg (17%), yellow oil.
1H NMR (250 MHz, CDCl3): d 7.26 (2H, d, J¼8.1 Hz,
C^CCarom.quat.(CHarom.)2), 7.07 (2H, d, J¼8.1 Hz,
CH3CH2Carom.quat.(CHarom.)2), 5.99e5.70 (1H, m, CH2CH]
CH2), 5.16e5.04 (2H, m, CH2CH]CH2), 3.73 (2H, s,
NHCH2), 3.13 (1H, dꢂd, J¼9.3, 3.2 Hz, CHCCl2), 2.89e
2.78 and 2.23e2.14 (2ꢂ1H, 2ꢂm, CH2CH]CH2), 2.54
(2H, q, J¼7.6 Hz, CH2CH3), 2.12 (3H, s, CH3), 1.57 (1H, s,
NH), 1.15 (3H, t, J¼7.6 Hz, CH2CH3).
13C NMR (62.90 MHz, CDCl3): d 136.3 (CH2CH]CH2),
117.0 (CH2CH]CH2), 94.9 (CCl2), 83.3 (2ꢂC^CCH2OMe),
80.1 (2ꢂC^CCH2OMe), 71.7 (CHCCl2), 60.0 (2ꢂNHCH2),
57.6 (2ꢂOMe), 40.8 (2ꢂCH2OMe), 35.8 (CH3CCl2), 32.1
(CH2CH]CH2).
13C NMR (62.90 MHz, CDCl3): d 143.5 (Carom.quat.Et),
134.1 (CH2CH]CH2), 130.5 (C^CCarom.quat.(Carom.)2),
126.8 (CH3CH2Carom.quat.(Carom.)2), 119.2 (C^CCarom.quat.),
117.3 (CH2CH]CH2), 94.0 (CCl2), 85.7 (C^CCarom.quat.),
83.0 (C^CCarom.quat.), 66.6 (CHCCl2), 38.5 (NHCH2), 36.0
IR (ATR, cmꢁ1): n 3283 (NH), 2418 (C^C), 1452, 1432
(C]C aromate), 1367 (HC]CH2).
MS (ESIþ): 336/334/332 ([Mþ5]þ/[Mþ3]þ/[Mþ1]þ¼8/
38/54), 234 ([Mꢁ97]þ).

S. Stas et al. / Tetrahedron 64 (2008) 3457e3463
3463
8. (a) Overman, L. E.; Kakimoto, M.-a.; Okazaki, M. E.; Meier, G. P.
J. Am. Chem. Soc. 1983, 105, 6622e6629; (b) Jacobsen, E. J.; Levin,
J.; Overman, L. E. J. Am. Chem. Soc. 1988, 110, 4329e4336; (c)
Overman, L. E.; Robertson, G. M.; Robichaud, A. J. J. Am. Chem. Soc.
1991, 113, 2598e2610; (d) Johnson, B. F.; Marrero, E. L.; Turley,
W. A.; Lindsay, H. A. Synlett 2007, 893e896; (e) Overman, L. E.;
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HRMS (ESI): m/z calcd for C16H23NO2Cl2þH: 331.1106;
found: 331.1125.
Acknowledgements
S.S. is a research assistant of the Fund for Scientific
Research-Flanders (Belgium). We would like to thank EBURON
ORGANICS for a generous gift of 3-butenylamine.
9. (a) Brummond, K. M.; Hong, S.-p. J. Org. Chem. 2005, 70, 907e916; (b)
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