Ring opening of cyclic N,O-acetals with allyltrimethylsilane under Lewis acidic conditions

Article abstract of DOI:10.1016/j.tet.2009.07.011

Five and six-membered cyclic N,O-acetals with N-carboxyalkyl and sulfonyl groups undergo clean and high yielding ring opening with allyltrimethylsilane in the presence of strong Lewis acids to give homoallylic amine derivatives.

Full text of DOI:10.1016/j.tet.2009.07.011

Tetrahedron 65 (2009) 7852–7858
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Ring opening of cyclic N,O-acetals with allyltrimethylsilane under Lewis
acidic conditions
*
Roderick W. Bates , Yongna Lu, Melody Peiling Cai
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, 21 Nanyang Link, Nanyang Technological University, Singapore 637371
a r t i c l e i n f o
a b s t r a c t
Article history:
Five and six-membered cyclic N,O-acetals with N-carboxyalkyl and sulfonyl groups undergo clean and
high yielding ring opening with allyltrimethylsilane in the presence of strong Lewis acids to give
homoallylic amine derivatives.
Received 11 March 2009
Received in revised form 20 June 2009
Accepted 2 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Available online 8 July 2009
1. Introduction
reductive amination and amide reduction, would not have been
suitable for our purpose as problems of alkene reduction or mi-
The reaction between cyclic O,O-acetals and silane reagents
under Lewis acidic conditions is now well known and has been
thoroughly studied.1 The corresponding reactions of cyclic
N,O-acetals, where the N bears an electron withdrawing group (PG),
have not, to our knowledge, been systematically studied (Scheme 1).
There have been several reports of the reactions of N,O-acetals of
various types and applications in total synthesis.2 In addition, the
CNRS group has reported reactions of N,O-acetals lacking an elec-
tron withdrawing substituent.3 The presumed intermediate in such
reactions, in the cases where PG is a carbonyl function, would be an
N-acyl iminium ion. These reactive intermediates have been shown
to be valuable in organic synthesis.4
gration could be anticipated. N,O-Acetal ring opening would di-
rectly deliver a homoallylic amine. We therefore made a systematic
study of this reaction.
We found that N,O-acetals could be easily prepared in almost
quantitative yield in many cases (Scheme 2). Stirring a mixture of
the amino alcohol derivative, an aldehyde, amberlyst-15 and 4 Å
molecular sieves in dichloromethane yielded the N,O-acetals in
generally excellent yields (Table 1) after filtration and evaporation.
The use of amberlyst-15 as the acid catalyst obviates the need for
any extraction.
RCHO
R
mol. svs.
PG
SO3H
NHPG
O
N
R
HO
n
SiMe3
Lewis acid
R
R
n
O
O
9 -16
n = 1 PG = Ts
PG = CO2Me
n = 2 PG = Ts
1
2
3
4
5
6
7
8
HO
O
PG = CO2Me
R
SiMe3
Lewis acid
PG = aloc
PG = CBZ
PG = Boc
PG = PhCO
O
NPG
HO
N
PG
Scheme 2.
Scheme 1.
2. Results and discussion
The reaction conditions for the synthesis of these N,O-acetals proved
to be compatible with almost all N-protecting groups employed: tosyl,
methoxycarbonyl, CBZ, Alloc and even t-Boc, with the exception of
amides. It was only when an amide was employed, the N-benzoyl
derivative, that a low yield of acetal was obtained (entry 16).
We became interested in this area following difficulties in
generating a homoallylic secondary amine, in which one or more of
the alkyl substituents was secondary. Several methods, such as
Acetalisation proved to be general for both aliphatic and aro-
matic aldehydes. Even paraformaldehyde lead to the formation of
the corresponding methylene acetal (entry 8), albeit at slower rate
due to the insolubility of the polymeric paraformaldehyde in the
* Corresponding author. Tel.: þ65 63168907; fax: þ65 67911961.
E-mail address: roderick@ntu.edu.sg (R.W. Bates).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.011

R.W. Bates et al. / Tetrahedron 65 (2009) 7852–7858
7853
reaction medium. In contrast, when crotonaldehyde, an
saturated aldehyde was used, no acetal could be isolated. Only a low
yield of an unstable acetal could be obtained using acetone.
a
,
b
-un-
possible to employ trimethylsilyl triflate as a Lewis acid catalyst,
however, this required a longer reaction time and higher temper-
ature, and gave a low yield.
Table 2
Use of alternative lewis acids
Table 1
Acetal formation and ring-opening reactions using TiCl4
Entry
n
R
PG
Lewis Acid
Yield/%
Entry Amino alcohol
derivative
n
R
PG
Acetal, yield (%) Homoallylic amine
derivative, yield (%)
1
2
3
4
2
2
2
2
Et
Et
Et
Et
Ts
Ts
Ts
Ts
BF3$OEt2
Me3SiOTf
TiCl4
33
30
99
98
1
2
3
4
5
6
7
8
1
1
2
2
3
3
3
3
4
4
4
4
5
6
7
8
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
Me
Et
Me
Et
Me
Et
Ph
H
Ts
Ts
9a, 99
9b, 81
17a, 92
17b, 88
18a, 80
18b, 92
19a, 99
19b, 99
19c, 32
19d, 99
20a, 99
20b, 99
20c, 67
20e, 99
21b, 98
22b, 63
23b, 66
d
SnCl4
CO2Me 10a, 73
CO2Me 10b, 87
Ts
Ts
Ts
Ts
CO2Me 12a, 85
CO2Me 12b, 87
CO2Me 12c, 80
11a, 82
11b, 99
11c, 91
11d, 94
Et
SiMe3
Lewis acid
Ts
N
O
NTs
HO
9
Me
Et
Ph
10
11
12
13
14
15
16
Et
19
11b
n-C5H11 CO2Me 12e, 76
Scheme 4.
Et
Et
Et
Et
Aloc
CBZ
t-Boc
Bz
13b, 99
14b, 86
15b, 86
16b, 30
Three additional substrates examined possessed chirality in
the amino alcohol chain (Scheme 5). 1-Aminobutan-3-ol 25 was
prepared by reduction of the corresponding nitrile.6 This nitrile
could be prepared either by the reaction between lithioacetoni-
trile and acetaldehyde, or by ring opening of propylene glycol
cyclic sulfate with cyanide. 3-Aminobutan-1-ol 26 was prepared
by Bouveault–Blanc reduction of ethyl 3-aminocrotonate.7 N,O-
Acetals 27b and 29b, each with an N-tosyl group, were obtained as
single diastereoisomers, which were crystalline solids. It is
interesting to note that X-ray structure determination shows that
for each acetal, the substituents adjacent to the N-Ts moiety prefer
an axial orientation, even in acetal 29b, which posses the methyl
and ethyl groups in a 1,3-diaxial arrangement (Figs. 1 and 2).8 N,O-
Acetal 28c with an alloc protecting group on the nitrogen atom
was also prepared.
The ring-opening reaction (Scheme 3) using titanium tetra-
chloride at low temperature proved to be clean and efficient for all
simple acetals derived from aliphatic substrates.
R
PG
N
n
PG
Lewis acid
O
N
O
R
n
9 - 16
PG
SiMe3
N
HO
n
R
The ring-opening reaction was tested using these three related
methyl substituted six-membered ring N,O-acetals (Table 3). While
chemical yields were, as expected, good,9 it was disappointing to
find that the reaction proceeded with a modest de for all three
substrates. It is notable that the highly selective opening of O,O-
acetals employs derivatives of diols that possess two sterochemical
centres, rather than the single chiral centre in this study.
17 - 23
Scheme 3.
Titanium tetrachloride was effective as a Lewis acid at ꢀ78 ꢁC. It
was gratifying to find that the large excesses typically employed in
the O,O-acetal chemistry1 were unnecessary. As little as 1.2 equiv
could be employed whilst still obtaining a good yield. The yields of
ring opened products were excellent, especially for the six-mem-
bered ring acetals. The methylene acetal derived from para-
formaldehyde also underwent efficient ring opening (entry 8). On
the other hand, N,O-acetals derived from benzaldehyde gave lower
yields (entries 7 and 11), accompanied by various by-products.
These observations apply equally to the N-tosyl and N-methoxy-
carbonyl substrates. The Aloc group was found to be completely
stable to the reaction conditions (entry 13). The yield of the ring-
opening products derived from the CBZ and t-Boc protected acetals
was lower, but still within a useful range (entries 14 and 15). It is
particularly notable that the t-Boc group survives a sequence of two
acidic steps.
The ring-opening reaction with allyltrimethylsilane was exam-
ined with a number of other Lewis acids using the six-membered
ring N,O-acetal 11b formed from propionaldehyde, with a tosyl
N-protecting group, as the test substrate (Table 2; Scheme 4). The
milder Lewis acids, titanium blend (Ti(Oi-Pr)4/TiCl4), Ti(Oi-Pr)4,
Yb(OTf)3$nH2O, In(OTf)3 and titanocene triflate, a Lewis acid
reported by Bosnich,5 proved to be ineffective, while boron tri-
fluoride etherate lead to a mixture of ring opening and acetal hy-
drolysis. Indium trichloride also resulted in destruction of the
acetal functional group. The only Lewis acid that could show similar
reactivity to titanium tetrachloride was tin(IV) chloride. It was
Et
PG
OH
O
N
Me
NHPG
Me
PG = Ts
27a
PG = Ts
27b
PG = alloc 28a
PG = alloc 28b
OH
Et
SiMe3
TiCl4
Me
N
PG
PG = Ts
27c
PG = alloc 28c
Et
Ts
OH Me
O
N
NHTs
Me
29a
29b
OH Me Et
SiMe3
TiCl4
N
Ts
29c
Scheme 5.

7854
R.W. Bates et al. / Tetrahedron 65 (2009) 7852–7858
chemical shift are expressed in parts per million relative to an in-
ternal standard. Peaks are assigned by consideration of chemical
shift values and coupling patterns. Melting points are uncorrected.
Infrared spectra were recorded using Nujol or neat.
4.2. General procedure for n-protected amino alcohols
Tosyl chloride (0.86 g, 4.50 mmol) was added slowly to a solution
of 1-aminobutan-3-ol (0.38 g, 4.28 mmol) and triethylamine (0.52 g,
5.14 mmol) in CH2Cl2 (10 mL) at 0 ꢁC. Then the reaction was allowed
to warm to room temperature and further stirred for 6 h. Water was
added and the mixture was extracted with dichloromethaneꢂ3. The
combined organic layer was washed with brine, dried over anhy-
drous Na2SO4 and concentrated in vacuo to give the sulfonamide
(0.93 g, 90%) as a colourless solid, which was used without
purification.
4.3. General procedure for the synthesis of cyclic N,O-acetals
Figure 1. X-ray structure of acetal 27b.
Acetaldehyde (67 mL, 1.2 mmol) was added to a solution of N-(3-
hydroxypropyl)-p-toluenesulfonamide (0.229 g, 1 mmol) in CH2Cl2
(10 mL) with trace of amberlyst-15 and 4 Å molecular sieves (pel-
lets, ca. 500 mg) at room temperature. The mixture was stirred at
room temperature for 2 h. It was filtered through Celite, and the
filtrate was evaporated in vacuo to give 2a (0.208 g, 82%) as a white
solid, which was used in the next step without purification.
4.4. General procedure for the ring-opening reaction of cyclic
N,O-acetals
A
solution of the cyclic N,O-acetal (0.19 mmol) and allyl-
trimethylsilane (0.22 mmol) in anhydrous dichloromethane (5 mL)
was cooled to ꢀ78 ꢁC. TiCl4 (0.22 mmol, 1 M in toluene) was
added dropwise at this temperature. The reaction mixture was stirred
at ꢀ78 ꢁC for 0.5 h. After the reaction was complete, the solution was
quenched with saturated aqueous NaHCO3 solution and the mixture
was extracted thrice with dichloromethane. The combined organic
layers were washed with water and brine, dried over anhydrous
Na2SO4, and concentrated in vacuo to give the protected amino alcohol.
Figure 2. X-ray structure of acetal 29b.
Table 3
Formation and ring opening of substituted N,O-acetals
Entry Amino alcohol derivative PG N,O-Acetal, yield (%) Homoallylic amine
derivative, yield
(%) (de %)
4.4.1. 2-Methyl-3-tosyloxazolidine (9a)
Yield 100%; colourless solid; mp 129–131 ꢁC; 1H NMR (300 MHz)
1
2
3
27a
28a
29a
Ts
aloc 28b, 76a
Ts 29b, 86
27b, 97
27c, 87% (26)
28c, 74% (40)
29c, 82% (29)
d
7.74 (2H, d, J¼8.1 Hz, Ar), 7.34 (2H, d, J¼8.1 Hz, Ar), 5.17 (1H, q, J¼5.5
Hz, CH), 3.93–3.87 (1H, m, CH2O), 3.47–3.42 (2H, m, CH2N), 3.39–3.32
(1H, m, CH2O), 2.44 (3H, s, ArCH3),1.48 (3H, d, J¼5.5 Hz, CH3–CH); 13
C
a
93:7 mixture of diastereoisomers.
NMR (100 MHz) d 144.1,134.2,129.9,127.8, 88.5, 65.2, 46.6, 22.1, 21.6;
IR (Nujol) 1340,1167, 673 cmꢀ1; MS (EI, m/z) 240 (MꢀH)þ, 226 (92%),
155 (82%), 91 (base peak). Anal. Calcd for C11H15O3NS: C, 54.75; H,
6.27; N, 5.80. Found: C, 54.61; H, 6.22; N, 5.78.
3. Conclusions
In conclusion, cyclic N,O-acetals provide an efficient and con-
venient access to a wide range of protected homoallylic amines.
Further investigation in this area is in hand, particularly using cyclic
iminium ion intermediates.
4.4.2. 2-Ethyl-3-tosyloxazolidine (9b)
Yield81%;colourlesssolid;mp71–72ꢁC;1HNMR(300MHz)
d7.74
(2H, d, J¼8.1 Hz, Ar), 7.33 (2H, d, J¼8.1 Hz, Ar), 5.06 (1H, dd, J¼4.5, 6.4
Hz, CH), 3.87–3.81 (1H, m, CH2O), 3.24–3.55 (3H, m), 2.44 (3H, s,
ArCH3), 1.88–1.65 (2H, m, CH3–CH2), 0.97 (3H, t, J¼7.4 Hz, CH3–CH2);
4. Experimental
13CNMR(75MHz)
d144.1,134.2,129.9,127.7, 92.5, 65.1, 46.6, 28.5, 21.5,
4.1. General procedures
8.5; IR (Nujol) 1342, 1165, 673 cmꢀ1; MS (EI, m/z) 254 (MꢀH)þ, 226
(base peak),155 (92%), 91 (96%). Anal. Calcd for C12H17O3NS: C, 56.45;
H, 6.71; N, 5.49. Found: C, 56.41; H, 6.72; N, 5.49.
All reactions were carried out under a dried nitrogen atmo-
sphere using oven-dried glassware (120 ꢁC), which was cooled
under vacuum. All commercially obtained reagents were used as
received. Amino alcohol derivatives 1,10 2,11 3,12 4,13 5,14 6,15 716 and
817 were prepared by standard procedures. Analytical TLC was
carried out on precoated plates (silica gel 60, F254). Column chro-
matography was performed with silica gel 60 (230–400 mesh). 1H
NMR spectra were recorded in CDCl3 at 300 or 400 MHz in CDCl3;
4.4.3. 3-Methoxycarbonyl-2-methyloxazolidine (10a)18
Yield 73%; colourless oil; 1H NMR (300 MHz)
d
5.23 (1H, q, J¼5.3
Hz, CH), 4.11–4.04 (1H, m, CH2O), 3.87 (1H, dd, J¼1.3, 7.3 Hz, CH2O),
3.72 (3H, s, OCH3), 3.73–3.58 (1H, m, CH2N), 3.45–3.37 (1H, m,
CH2N), 1.41–1.40 (2H, m, CH2–CH2–CH2); 13C NMR (100 MHz)
d
154.0, 86.1, 65.4, 52.4, 44.5, 20.0; IR (neat) 1701, 1458, 1394, 771

R.W. Bates et al. / Tetrahedron 65 (2009) 7852–7858
7855
cmꢀ1; MS (EI, m/z) 144 (MꢀH)þ, 130 (base peak); HRMS m/z calcd
for C6H10O3N (MꢀH)þ 144.0655, found 144.0654.
Hz, NCH2), 3.71 (3H, s, OCH3), 3.69–3.66 (1H, m, CH2O), 3.17 (1H, dt,
J¼3.6, 12.9 Hz, CH2N), 2.04–1.87 (2H, m, CH2–CH2–CH2), 1.85–1.37
(2H, m, CH3CH2), 0.91 (3H, t, J¼7.4 Hz, CH3CH); 13C NMR (75 MHz)
4.4.4. 3-Methoxycarbonyl-2-ethyloxazolidine (10b)
d 155.3, 83.4, 59.4, 37.1, 25.3, 22.0, 9.1; IR (neat) 2966, 2876, 1701,
Yield 87%; colourless oil; 1H NMR (400 MHz)
d
5.09 (1H, br dd,
1450, 1279, 768 cmꢀ1; MS (EI, m/z) 174 (MþH)þ, 144 (base peak), 88
(24%); HRMS m/z calcd for C8H15O3N (M)þ 173.1046, found
173.1045.
J¼2.5, 6.3 Hz, CH), 4.90–4.83 (1H, m, CH2O), 4.09–4.02 (1H, m,
CH2O), 3.72 (3H, s, OCH3), 3.73–3.68 (1H, m, CH2N), 3.40–3.32 (1H,
m, CH2N), 1.83–1.60 (2H, m, CH2–CH2–CH2), 0.92 (3H, t, J¼7.4 Hz,
CH3CH2); 13C NMR (100 MHz)
d
154.2, 90.0, 65.3, 52.3, 44.9, 26.5,
4.4.11. 3-Methoxycarbonyl-2-phenyl-1,3-oxazinane (12c)
7.9; IR (neat) 1712, 1454, 1382, 769 cmꢀ1; MS (EI, m/z) 158 (MꢀH)þ,
130 (base peak); HRMS m/z calcd for C7H12O3N (MꢀH)þ 158.0812,
found 158.0813.
Yield 80%; colourless oil; 1H NMR (400 MHz)
d 7.43–7.31 (5H,
m, Ar), 6.73 (1H, s, CH), 4.17 (1H, br d, J¼11.0 Hz, CH2O), 3.78 (3H,
s, OCH3), 3.76–3.68 (2H, m), 3.08 (1H, dt, J¼3.1, 13.1 Hz, CH2N),
2.39–1.96 (1H, m, CH2–CH2–CH2), 1.38 (1H, d, J¼13.2 Hz, CH2–
4.4.5. 2-Methyl-3-tosyl-1,3-oxazinane (11a)
CH2–CH2); 13C NMR (75 MHz)
d 156.1, 136.7, 128.9, 128.0, 126.9,
Yield 82%; colourless solid; mp 92–93 ꢁC; 1H NMR (400 MHz)
82.2, 60.4, 53.0, 38.3, 25.4; IR (neat) 1709, 1456, 1026, 721 cmꢀ1
;
d
7.78 (2H, d, J¼8.2 Hz, Ar), 7.30 (2H, d, J¼8.2 Hz, Ar), 5.62 (1H, q,
MS (EI, m/z) 221 (Mþ), 162 (76%), 105 (62%), 144 (base peak), 155
(64%), 91.27 (68%); HRMS m/z calcd for C12H15O3N (M)þ 221.1046,
found 221.1042.
J¼6.3 Hz, CH), 3.89 (1H, dt, J¼3.3, 11.4 Hz, CH2O), 3.71–3.67 (1H, m,
CH2O), 3.59–3.51 (2H, m, CH2N), 2.43 (3H, s, ArCH3), 1.55 (3H, d,
J¼4.6 Hz, CH3–CH), 1.40–1.24 (2H, m, CH2–CH2–CH2); 13C NMR (75
MHz)
d
143.3, 138.1, 129.7, 127.4, 80.8, 59.5, 39.4, 23.5, 21.5, 17.3; IR
4.4.12. 3-Methoxycarbonyl-2-pentyl-1,3-oxazinane (12e)
(Nujol) 1340, 1153, 858, 760, 665 cmꢀ1; MS (EI, m/z) 254 (MꢀH)þ,
240 (base peak), 155 (64%), 91 (68%). Anal. Calcd for C12H17O3NS: C,
56.45; H, 6.71; N, 5.49. Found: C, 56.30; H, 6.66; N, 5.47.
Yield 76%; colourless oil; 1H NMR (400 MHz)
d
5.47 (1H, t, J¼7.1
Hz, CH), 4.03 (1H, dd, J¼4.5, 13.5 Hz, CH2O), 3.87 (1H, dt, J¼3.4, 23.1
Hz, NCH2), 3.68 (3H, s, OCH3), 3.70–3.61 (1H, m, CH2O), 3.15 (1H, dt,
J¼3.6, 13.1 Hz, CH2N), 1.92–1.81 (2H, m, CH–CH2–CH2); 1.74–1.68
(1H, m, OCH2–CH2–CH2N), 1.49 (1H, td, J¼2.5, 10.6 Hz, OCH2–CH2–
CH2N), 1.29–1.15 (6H, m), 0.87 (3H, t, J¼3.7 Hz, CH2CH3); 13C NMR
4.4.6. 2-Ethyl-3-tosyl-1,3-oxazinane (11b)
Yield 100%; colourless solid; mp 53–54 ꢁC; 1H NMR (400 MHz)
d
7.79 (2H, d, J¼8.1 Hz, Ar), 7.30 (2H, d, J¼8.1 Hz, Ar), 5.38 (1H, t,
(75 MHz) d 155.2, 82.2, 59.4, 52.6, 37.1, 31.4, 28.8, 25.3, 24.4, 22.5,
J¼7.2 Hz, CH), 3.84–3.72 (2H, m, CH2O), 3.52–3.40 (2H, m, CH2N),
2.42 (3H, s, ArCH3), 2.03–1.88 (2H, m, CH3–CH2), 1.35–1.28 (1H, m,
CH2–CH2–CH2), 1.14 (1H, br d, J¼13.4 Hz, CH2–CH2–CH2), 0.95 (3H, t,
13.9; IR (neat) 1703, 1449, 1410, 1277, 770 cmꢀ1; MS (EI, m/z) 216
(MþH)þ, 144 (base peak); HRMS m/z calcd for C11H22O3N (MþH)þ
216.1594, found 216.1598.
J¼7.4 Hz, CH3–CH2); 13C NMR (75 MHz)
d 140.8, 135.8, 127.2, 125.0,
82.4, 56.4, 36.6, 20.5, 20.3, 19.1, 7.0; IR (Nujol) 1338, 1155, 964, 875,
663 cmꢀ1; MS (EI, m/z) 268 (MꢀH)þ, 240 (base peak), 155 (80%), 91
(88%). Anal. Calcd for C13H19O3NS: C, 57.97; H, 7.11; N, 5.20. Found:
C, 58.14; H, 7.32; N, 5.00.
4.4.13. 3-Allyloxycarbonyl-2-ethyl-1,3-oxazinane (13b)
Yield 100%; colourless oil; 1H NMR (300 MHz)
d 6.00–5.87 (1H,
m, CH]CH2), 5.46 (1H, t, J¼7.1 Hz, CH), 5.33–5.19 (2H, m, CH2]CH),
4.61 (2H, dd, J¼5.5, 1.4 Hz, CH2–CH]CH2), 4.08 (1H, dd, J¼5.4, 13.6
Hz, OCH2), 3.90 (1H, dt, J¼3.5, 11.6 Hz, NCH2), 3.74–3.69 (1H, m,
OCH2), 3.18 (1H, dt, J¼3.6, 13.0 Hz, CH2N), 2.00–1.76 (2H, m,
CH2CH3), 1.59–1.56 (2H, m, CH2CH2CH2), 0.92 (3H, t, J¼4.4 Hz,
4.4.7. 2-Phenyl-3-tosyl-1,3-oxazinane (11c)19
Yield 91%; colourless solid; 1H NMR (300 MHz)
d 7.90 (2H, d,
J¼8.3 Hz, Ar), 7.51–7.34 (7H, m, Ar), 6.69 (1H, s, CH), 3.84 (1H, dd,
J¼4.2, 14.5 Hz, CH2O), 3.72 (1H, td, J¼2.8, 12.0 Hz, CH2N), 3.59 (1H,
dd, J¼4.2, 11.6 Hz, CH2O), 3.31 (1H, td, J¼2.8, 14.1 Hz, CH2N), 2.46
(3H, s, ArCH3), 1.49–1.32 (2H, m, CH2–CH2–CH2); 13C NMR (75 MHz)
CH2CH3); 13C NMR (100 MHz)
d 154.5, 132.9, 117.4, 83.4, 66.0, 59.5,
37.1, 25.3, 22.1, 9.2; IR (neat) 1694, 1441, 1416, 1016, 766 cmꢀ1; MS
(EI, m/z) 200 (MþH)þ, 170 (base peak), 126 (16%), 98 (36%), 70
(18%); HRMS calcd for C10H18O3N (MþH)þ 200.1821, found
200.1273.
d
143.6, 138.1, 136.1, 129.8, 129.0, 128.2, 127.6, 127.2, 83.7, 60.0, 39.8,
23.1, 21.6.
4.4.14. 3-Benzyloxycarbonyl-2-ethyl-1,3-oxazinane (14b)
4.4.8. 3-Tosyl-1,3-oxazinane (11d)20
Yield 86%; colourless oil; 1H NMR (300 MHz)
d 7.36–7.33 (5H, m,
Yield 94%; colourless solid; 1H NMR (400 MHz)
d
7.78 (2H, d,
Ar), 5.48 (1H, t, J¼7.1 Hz, CH), 5.15 (2H, s, CH2), 4.10 (1H, dd, J¼5.1,
13.5 Hz, OCH2), 3.89 (1H, dt, J¼3.5,11.6 Hz, NCH2), 3.73–3.69 (1H, m,
OCH2), 3.19 (1H, dt, J¼3.7, 13.0 Hz, NCH2), 1.97–1.85 (2H, m,
CH3CH2), 1.83–1.78 (1H, m, CH2CH2CH2), 1.58–1.50 (1H, m,
CH2CH2CH2), 0.90 (3H, t, J¼7.4 Hz, CH3CH2); 13C NMR (100 MHz)
J¼8.1 Hz, Ar), 7.32 (2H, d, J¼8.1 Hz, Ar), 4.94 (1H, s, CH2), 3.71 (2H, t,
J¼5.3 Hz, CH2O), 3.53 (2H, t, J¼5.7 Hz, CH2N), 2.44 (3H, s, ArCH3),
1.35 (2H, tt, J¼5.3, 5.7 Hz, CH2–CH2–CH2); 13C NMR (75 MHz)
d
143.4, 136.8, 129.5, 127.3, 78.1, 67.1, 44.1, 23.3, 21.2.
d
154.6, 136.6, 128.5, 128.0,127.8, 83.5, 67.1, 59.5, 37.2, 25.3, 22.1, 9.2;
4.4.9. 3-Methoxycarbonyl-2-methyl-1,3-oxazinane-3-
IR (neat) 1697, 1454, 1418, 1016, 698 cmꢀ1; MS (EI, m/z) 250
(MþH)þ, 220 (46%), 176 (50%), 91 (base peak); HRMS calcd for
C14H19O3N1 (M)þ 249.1359, found 249.1358.
carboxylate (12a)
Yield 85%; colourless oil; 1H NMR (400 MHz)
d
5.68 (1H, q, J¼6.2
Hz, CH), 4.03–3.91 (2H, m, CH2O), 3.71 (3H, s, OCH3), 3.73–3.66 (1H,
m, CH2N), 3.23 (1H, dt, J¼3.8, 12.6 Hz, CH2N), 1.88–1.82 (1H, m,
CH2–CH2–CH2), 1.58–1.53 (1H, m, CH2–CH2–CH2), 1.44 (3H, d, J¼6.2
4.4.15. 3-tert-Butoxycarbonyl 2-ethyl-1,3-oxazinane (15b)
Yield 86%; colourless oil; 1H NMR (300 MHz)
d
5.39 (1H, t, J¼7.1
Hz, CH3CH); 13C NMR (100 MHz)
d
154.9, 79.1, 59.6, 52.6, 36.9, 25.3,
Hz, CH), 4.03 (1H, dd, J¼5.1, 13.7 Hz, OCH2), 3.87 (1H, dt, J¼3.5, 11.6
Hz, NCH2), 3.71–3.68 (2H, m, OCH2), 3.09 (1H, dt, J¼3.6, 13.2 Hz,
NCH2), 1.92–1.78 (2H, m, CH3CH2), 1.55–1.44 (2H, m, CH2–CH2CH2),
1.46 (9H, s, C(CH3)3), 0.90 (3H, t, J¼7.4 Hz, CH3CH2); 13C NMR (75
15.9; IR (neat) 1694, 1445, 1279, 770 cmꢀ1; MS (EI, m/z) 158
(MꢀH)þ, 144 (base peak), 88 (39%); HRMS m/z calcd for C7H12O3N
(MꢀH)þ 158.0812, found 158.0814.
MHz)
d 153.9, 83.3, 79.8, 59.4, 36.6, 28.3, 25.3, 22.0, 9.2; IR (neat)
4.4.10. 3-Methoxycarbonyl-2-ethyl-1,3-oxazinane (12b)
1694, 1477, 1458, 1411, 1366, 1155 cmꢀ1; MS (EI, m/z) 216 (MþH)þ,
186 (24%), 130 (65%), 116 (50%), 86 (base peak); HRMS calcd for
C11H21O3N (M)þ 215.1516, found 215.1523.
Yield 87%; colourless oil; 1H NMR (300 MHz)
d
5.42 (1H, t, J¼7.2
Hz, CH), 4.06 (1H, dd, J¼5.2, 13.5 Hz, CH2O), 3.89 (1H, dt, J¼3.5, 11.6

7856
R.W. Bates et al. / Tetrahedron 65 (2009) 7852–7858
4.4.16. 3-Benzoyl-2-ethyl-1,3-oxazinane (16b)
NMR (75 MHz; CDCl3) d 143.2, 137.8, 134.8, 129.7, 127.0, 117.4, 59.2,
Yield 30%; colourless oil; 1H NMR (300 MHz)
d
7.40 (5H, m, Ar),
53.9, 40.2, 39.9, 34.0, 21.5, 18.4; IR (neat) 3524, 2972, 2930, 1599,
1456,1337,1153, 658 cmꢀ1; MS (EI, m/z) 256 (MꢀCH2CH]CH2), 212
(base peak), 155 (25%), 91 (28%); HRMS calcd for C12H18O3NS
256.1002 (MꢀCH2CH]CH2)þ, found 256.1005.
5.42 (1H, br, CH), 4.20 (1H, br, OCH2), 3.96 (1H, dt, J¼3.2, 11.8 Hz,
NCH2), 3.77 (1H, dd, J¼5.3,11.7 Hz, OCH2), 3.25 (1H, dt, J¼3.3,13.2 Hz,
NCH2), 2.11–2.01 (2H, m, CH3CH2), 1.99–1.82 (1H, m, CH2CH2CH2),
1.58–1.54 (1H, m, CH2CH2CH2), 0.88 (3H, t, J¼7.4 Hz, CH3CH2); 13C
NMR (75 MHz)
d
170.5,135.9,129.7,128.5,126.8, 59.5, 39.9, 38.0, 25.8,
4.4.22. N-(Hex-5-en-3-yl)-N-(3-hydroxypropyl)-p-
21.9, 9.2; IR (neat) 2968, 2936, 2876, 1643, 1600, 1446, 1417, 1283,
880, 702 cmꢀ1; MS (EI, m/z) 220 (MþH)þ,190 (68%),105 (base peak);
HRMS calcd for C13H17O2N (M)þ 219.1254, found 219.1251.
toluenesulfonamide (19b)
Yield 100%; colourless oil; 1H NMR (300 MHz)
d 7.71 (2H, d,
J¼8.3 Hz, Ar), 7.28 (2H, d, J¼8.3 Hz, Ar), 5.58–5.53 (1H, m, CH2]CH),
4.97 (1H, d, J¼4.1 Hz, CH2]CH), 4.92 (1H, br, CH2]CH), 3.75 (2H, br,
OCH2), 3.64–3.60 (1H, m, CHN), 3.28–3.22 (2H, m, NCH2), 2.42 (3H,
s, ArCH3), 2.22–2.01 (2H, m, CH2CH]CH2), 1.87–1.79 (2H, m,
OCH2CH2CH2), 1.57–1.50 (1H, m, CH3CH2), 1.38–1.25 (1H, m,
CH3CH2), 0.79 (3H, t, J¼7.3 Hz, CH3CH2); 13C NMR (75 MHz; CDCl3)
4.4.17. N-(2-Hydroxyethyl)-N-(pent-4-en-2-yl)-p-
toluenesulfonamide (17a)
Yield 92%; colourless oil; 1H NMR (400 MHz)
d
7.63 (2H, d, J¼8.1
Hz, Ar), 7.21 (2H, d, J¼8.1 Hz, Ar), 5.60–5.50 (1H, m, CH2]CH), 4.94
(1H, d, J¼1.5 Hz, CH2]CH), 4.91 (1H, s, CH2]CH), 3.93–3.88 (1H, m,
CHN), 3.73–3.70 (2H, br, OCH2), 3.18–3.10 (2H, m, NCH2), 2.70 (1H,
br, OH), 2.33 (3H, s, ArCH3), 2.33–1.98 (2H, m, CH2CH]CH2), 0.87
d
143.1, 137.9, 135.1, 129.5, 127.1, 117.2, 60.3, 59.5, 40.4, 38.1, 34.0,
25.8, 21.5, 11.4; IR (neat) 3524, 2966, 2936, 2877, 1599, 1456, 1383,
1334, 1153, 658 cmꢀ1; MS (EI, m/z) 270 (MꢀCH2CH]CH2)þ, 226
(45%), 155 (38%), 91 (60%); HRMS calcd for C13H20O3NS 270.1158
(MꢀCH2CH]CH2)þ, found 270.1158.
(3H, d, J¼6.7 Hz, CH3CH); 13C NMR (100 MHz; CDCl3)
d 143.4, 137.0,
134.7, 129.6, 127.1, 117.4, 62.6, 53.9, 45.1, 39.8, 21.4, 18.0; IR (neat)
3524, 2976, 2930,1597,1456, 1337, 1153, 658 cmꢀ1; MS (EI, m/z) 284
(MþH)þ, 242 (base peak),155 (42%), 91 (62%), 70 (98%); HRMS calcd
for C14H20O3NS 282.1158 (MꢀH)þ, found 282.1144.
4.4.23. N-(3-Hydroxypropyl)-N-(1-phenylbut-3-enyl)-p-
toluenesulfonamide (19c)
Yield 32%; colourless oil; 1H NMR (300 MHz; CDCl3)
d 7.71 (2H,
4.4.18. N-(Hex-5-en-3-yl)-N-(2-hydroxyethyl)-p-
d, J¼8.3 Hz, Ar), 7.31–7.24 (7H, m, Ar), 5.63–5.49 (1H, m, CH]CH2),
5.06–5.01 (1H, m, PhCH), 4.96–4.91 (2H, m, CH]CH2), 3.53–3.46
(2H, m, CH2O), 3.24–3.18 (2H, m, CH2N), 2.88–2.78 (1H, m,
CH2CH]CH2), 2.41 (3H, s, Ar), 2.40–2.33 (1H, m, CH2CH]CH2), 2.03
(1H, br, OH), 1.47–1.36 (2H, m, CH2CH2CH2); 13C NMR (100 MHz)
toluenesulfonamide (17b)
Yield 88%; colourless oil; 1H NMR (300 MHz)
d
7.73 (2H, d, J¼8.1
Hz, Ar), 7.30 (2H, d, J¼8.1, Ar), 5.65–5.56 (1H, m, CH2]CH), 4.99 (1H,
d, J¼6.6 Hz, CH2]CH), 4.95 (1H, s, CH2]CH), 3.84–3.37 (2H, m,
OCH2), 3.70–3.66 (1H, m, CHN), 3.24–3.19 (2H, m, NCH2), 2.43 (3H,
s, ArCH3), 2.17–1.98 (2H, m, CH2CH]CH2), 1.57–1.48 (1H, m,
CH3CH2), 1.33–1.23 (1H, m, CH3CH2), 0.83 (3H, t, J¼7.4 Hz, CH3CH2);
d
143.3, 137.8, 134.2, 129.7, 128.5, 128.4, 128.0, 127.2, 117.7, 60.2, 59.0,
40.8, 35.2, 32.9, 21.5; IR (neat) 3524, 3065, 2947, 2878, 1599, 1454,
1335, 1157, 662 cmꢀ1; MS (EI, m/z) 318 (MꢀCH2CH]CH2)þ, 91 (base
peak); HRMS calcd for C17H20O3NS 318.1158 (MꢀCH2CH]CH2)þ,
found 318.1159.
13C NMR (75 MHz; CDCl3)
d 143.4, 137.3, 135.0, 123.0, 127.3, 117.4,
62.6, 60.5, 45.6, 37.8, 25.8, 21.5, 11.3; IR (neat) 3524, 2966, 2933,
2877, 1597, 1456, 1383, 1335, 1155, 658 cmꢀ1; MS (EI, m/z) 298
(MþH)þ, 256 (base peak), 155 (45%), 116 (44%), 91 (62%), 84 (85%);
HRMS calcd for C15H22O3NS 296.1315 (MꢀH)þ, found 296.1320.
4.4.24. N-(But-3-enyl)-N-(3-hydroxypropyl)-p-toluene-
sulfonamide (19d)
Yield 100%; colourless oil; 1H NMR (300 MHz)
d
7.67 (2H, d, J¼8.1
4.4.19. Methyl 2-hydroxyethyl(pent-4-en-2-yl)carbamate (18a)
Hz, Ar), 7.28 (2H, d, J¼8.1 Hz, Ar), 5.68–5.55 (1H, m, CH2]CH), 5.00–
4.93 (2H, m, CH2]CH), 3.66 (2H, t, J¼5.7 Hz, OCH2), 3.21–3.09 (4H,
m, NCH2CH2CH2CH, NCH2(CH2)3), 2.35 (3H, s, ArCH3), 2.25–2.17 (2H,
m, CH2CH]CH2), 1.70–1.67 (2H, m, OCH2CH2CH2N); 13C NMR (75
Yield 80%; colourless oil; 1H NMR (400 MHz)
d 5.69 (1H, br,
CH2]CH), 5.07–4.96 (2H, m, CH2]CH), 4.11 (1H, br, HOCH2), 3.69
(5H, br, OCH3þCH2OHþNH), 3.35–3.28 (2H, m, CH2N), 2.27–2.18
(2H, m, CH2CH]CH2), 0.88 (3H, d, J¼7.4 Hz, CH3CH); 13C NMR (75
MHz; CDCl3) d 143.3, 136.4, 134.5, 129.7, 127.0, 117.1, 58.7, 48.3, 45.1,
MHz)
d
159.8, 135.0, 117.3, 63.5, 52.7, 52.3, 45.8, 39.3, 18.8; IR (neat)
33.2, 31.2, 21.4; IR (neat) 3437, 2930, 2876, 1641, 1599, 1458, 1155,
918 cmꢀ1; MS (EI, m/z) 284 (MþH)þ, 242 (MꢀCH2CH]CH2)þ, 198
(base peak), 155 (20%), 91 (22%); HRMS calcd for C11H16O3NS
242.0845 (MꢀCH2CH]CH2)þ, found 242.0838.
3410, 1702, 1453 cmꢀ1; MS (EI, m/z) 188 (MþH)þ, 146 (base peak),
114 (28%), 70 (26%); HRMS calcd for C9H18O3N 188.1281 (MþH)þ,
found 188.1273.
4.4.20. Methyl hex-5-en-3-yl(2-hydroxyethyl)carbamate (18b)
4.4.25. Methyl 3-hydroxypropyl(pent-4-en-2-yl)carbamate (20a)
Yield 92%; colourless oil; 1H NMR (300 MHz)
d
5.72–5.68 (1H, m,
Yield 100%; colourless oil; 1H NMR (300 MHz)
d 5.73–5.63 (1H,
CH2]CH), 5.06–5.01 (1H, m, CH2]CH), 5.01 (1H, s, CH2]CH), 3.87
(1H, br, CH2OH), 3.69 (5H, br, OCH3þCH2OHþNH), 3.30–3.22 (1H, m,
CH2N), 2.20 (2H, m, CH2CH]CH2), 1.50–1.47 (2H, m, CH3CH2), 0.88
m, CH2]CH), 5.06–4.98 (2H, m, CH2]CH), 3.67 (3H, s, OCH3), 3.62–
3.47 (1H, br, CH2O), 3.31 (2H, br, CH2N), 2.32–2.19 (2H, m,
CH2CH]CH2), 1.68 (2H, br, CH2CH2CH2), 1.16 (3H, d, J¼6.9 Hz,
(3H, t, J¼7.4 Hz, CH3CH2); 13C NMR (75 MHz)
d
159.4, 135.0, 117.2,
CH3CH); 13C NMR (75 MHz; CDCl3)
d 158.3, 135.1, 117.1, 59.0, 58.8,
63.2, 58.5, 52.8, 45.9, 37.8, 25.9,11.0; IR (neat) 3437, 2965,1712,1469
cmꢀ1; MS (EI, m/z) 202 (MþH)þ, 160 (base peak), 128 (82%), 84
(24%); HRMS calcd for C10H19O3N1 201.1359 (M)þ, found 201.1359.
52.5, 40.3, 39.4, 32.6, 18.9; IR (neat) 3435, 2955, 2930, 2874, 1694,
1057 cmꢀ1; MS (EI, m/z) 202 (MþH)þ, 160 (MꢀCH2CH]CH2, 58%),
116 (base peak), 84 (24%); HRMS calcd for C10H19O3N 201.1359
(M)þ, found 201.1359.
4.4.21. N-(3-Hydroxypropyl)-N-(pent-4-en-2-yl)-p-
toluenesulfonamide (19a)
4.4.26. Methyl hex-5-en-3-yl(3-hydroxypropyl)carbamate (20b)
Yield 100%; colourless oil; 1H NMR (300 MHz)
d
7.70 (2H, d,
Yield 100%; colourless oil; 1H NMR (300 MHz)
d 5.77–5.65 (1H,
J¼8.3 Hz, Ar), 7.28 (2H, d, J¼8.0 Hz, Ar), 5.68–5.54 (1H, m, CH2]CH),
5.03 (1H, d, J¼1.5 Hz, CH2]CH), 5.00 (1H, s, CH2]CH), 3.96–3.89
(1H, m, CHN), 3.75 (2H, t, J¼6.8 Hz, OCH2), 3.41–3.30 (2H, m, NCH2),
2.41 (3H, s, ArCH3), 2.27–2.06 (2H, m, CH2CH]CH2), 1.84 (2H,
quint., J¼6.3 Hz, OCH2CH2CH2), 1.00 (3H, d, J¼6.8 Hz, CH3CH); 13C
m, CH2]CH), 5.05 (1H, d, J¼7.9 Hz, CH2]CH), 5.01 (1H, s, CH2]CH),
3.92 (1H, br, NCH), 3.71 (3H, s, OCH3), 3.72–3.60 (2H, m, CH2O),
3.36–3.17 (1H, m, CH2N), 2.30–2.26 (2H, m, CH2CH]CH2), 1.72–1.58
(1H, m, CH2CH2CH2), 1.56–1.50 (2H, m, CH3CH2), 0.88 (3H, t, J¼7.4
Hz, CH3CH2); 13C NMR (100 MHz; CDCl3)
d 158.8, 135.2, 117.1, 60.2,

R.W. Bates et al. / Tetrahedron 65 (2009) 7852–7858
7857
59.0, 52.7, 40.6, 38.0, 32.4, 26.0, 11.2; IR (neat) 3439, 3076, 2961,
2875,1693,1060, 916, 773 cmꢀ1; MS (EI, m/z) 216 (MþH)þ,174 (67%),
142 (32%), 130 (base peak); HRMS calcd for C11H20O3N1 214.1438
(MꢀH)þ, found 214.1440.
72 (58%); HRMS calcd for C11H22O3N 216.1594 (MꢀCH2CH]CH2)þ,
found 216.1590.
4.4.32. N-(3-Hydroxybutyl)-p-toluenesulfonamide (27a)
Yield 90%; colourless solid; 1H NMR (400 MHz)
d
7.75 (2H, d, J¼8.1
4.4.27. Methyl 3-hydroxypropyl(1-phenylbut-3-enyl)-
Hz, Ar), 7.31 (2H, d, J¼8.1 Hz, Ar), 5.08 (1H, br, NH), 3.94–3.91 (1H, m,
CH), 3.19–3.15 (1H, m, CH2N), 3.03–3.00 (1H, m, CH2N), 2.43 (3H, s,
Ar–CH3), 1.68–1.52 (2H, m, NCH2–CH2–CHO), 1.17 (3H, d, J¼6.2 Hz,
carbamate (20c)
Yield 67%; colourless oil; 1H NMR (300 MHz)
d 7.28–7.33 (5H, m,
Ar), 5.84–5.71 (1H, m, CH2]CH), 5.29 (1H, br, NCH), 5.29–5.06 (2H,
m, CH2]CH), 3.71 (3H, s, OCH3), 3.41 (2H, t, J¼5.7 Hz, CH2O), 3.27–
3.20 (2H, m, CH2N), 2.78–2.72 (2H, m, CH2CH]CH2), 1.59 (1H, br,
CH2CH2CH2), 1.40 (1H, br, CH2CH2CH2); 13C NMR (75 MHz; CDCl3)
CH3–CH); 13C NMR (75 MHz)
d 143.1, 136.5, 129.5, 126.8, 65.8, 40.4,
37.5, 23.2, 21.3; IR (Nujol) 3282, 1598, 1157, 816, 663 cmꢀ1; MS (EI,
m/z) 244 (MþH)þ, 184 (39%), 155 (base peak), 91 (98%); HRMS m/z
calcd for C11H17O3NS (M)þ 243.0924, found 243.0929.
d
158.0, 139.5, 134.7, 128.5, 128.0, 127.8, 117.6, 59.0, 58.6, 52.9, 40.1,
35.3, 32.1; IR (neat) 3443, 2954, 1672, 1469, 1447, 1404, 1057, 702
cmꢀ1; MS (EI, m/z) 264 (MþH)þ, 222 (74%), 118 (72%), 121 (52%), 91
(base peak); HRMS calcd for C15H21O3N 263.1516 (MꢀH)þ, found
263.1507.
4.4.33. trans-2-Ethyl-6-methyl-3-tosyl-1,3-oxazinane (27b)
Yield 81%; colourless solid; mp 80–82 ꢁC; 1H NMR (400 MHz)
d
7.80 (2H, d, J¼8.1 Hz, Ar), 7.30 (2H, d, J¼8.1 Hz, Ar), 5.49 (1H, t,
J¼7.4 Hz, OCHN), 3.86–3.81 (1H, m, CH2N), 3.79–3.74 (1H, m, CH–
CH3), 3.45–3.41 (1H, m, CH2N), 2.43 (3H, s, ArCH3), 2.03–1.84 (2H,
m, CH–CH2–CH3), 1.14 (1H, br d, J¼13.4 Hz, CH–CH2–CH2); 0.96 (3H,
t, J¼7.4 Hz, CH3–CH2), 0.89 (3H, d, J¼6.0 Hz, CH3–CH); 13C NMR (100
4.4.28. Methyl 3-hydroxypropyl(non-1-en-4-yl)carbamate (20e)
Yield 100%; colourless oil; 1H NMR (400 MHz)
d 5.71–5.64 (1H, m,
CH2]CH), 5.00–5.04 (2H, m, CH2]CH), 4.01–3.83 (1H, m, CHN), 3.69
(3H, s, OCH3), 3.69–3.57 (2H, m, CH2O), 3.37–3.14 (2H, m, NCH2),
2.29–2.19 (2H, m, CH2CH]CH2), 1.67–1.69 (2H, m, OCH2CH2CH2N),
1.48–1.46 (2H, br, CH2CH2CH), 1.27–1.25 (6H, br, CH2CH2CH2), 0.86
MHz) d 143.2, 138.1, 129.4, 127.6, 84.8, 63.6, 38.9, 29.8, 23.0, 21.6,
21.4, 9.56; IR (Nujol) 1335, 1157, 675 cmꢀ1; MS (EI, m/z) 282
(MꢀH)þ, 254 (base peak), 155 (51%), 91 (45%). Anal. Calcd for
C14H21O3NS: C, 59.34; H, 7.47; N, 4.94. Found: C, 59.33; H, 7.53; N,
4.83.
(3H, t, J¼6.6 Hz, CH3CH2); 13C NMR (100 MHz; CDCl3)
d 158.8, 135.2,
117.1, 59.0, 57.2, 52.7, 40.0, 38.2, 33.1, 32.5, 31.6, 26.2, 22.6, 14.0; IR
(neat) 3418, 2954, 2928, 2858,1694,1061, 914, 773 cmꢀ1; MS (EI, m/z)
258 (MþH)þ, 216 (76%), 184 (44%),172 (48%), 102 (base peak); HRMS
calcd for C14H27O3N 257.1985 (M)þ, found 257.1982.
4.4.34. N-(Hex-5-en-3-yl)-N-(3-hydroxybutyl)-p-toluene
sulfonamide (27c) (mixture of isomers)
Yield 87%; colourless oil; 1H NMR (400 MHz)
d
7.69 (4H, d, J¼8.3
Hz, Ar), 7.27 (4H, d, J¼8.3 Hz, Ar), 5.54–5.60 (0.58H, m, CH2]CH),
5.42–5.34 (1H, m, CH2]CH), 4.99–4.87 (3H, m, CH2]CH), 3.95–
3.93 (2H, m), 3.60–3.58 (2H, m), 3.36–3.29 (2H, m), 3.15–3.09 (2H,
m), 2.42 (6H, s, ArCH3), 2.17–2.08 (2H, m), 1.92–1.77 (2H, m), 1.64–
1.35 (8H, m), 1.26–1.19 (6H, m), 0.86 (3H, t, J¼7.3 Hz, CH3CH2), 0.69
(1.8H, t, J¼7.3 Hz, CH3CH2).
4.4.29. Allyl hex-5-en-3-yl(3-hydroxypropyl)carbamate (21b)
Yield 98%; colourless oil; 1H NMR (300 MHz)
d 5.94–5.85 (1H, m,
OCH2CH2]CH), 5.76–5.63 (1H, m, CHCH2CH2]CH), 5.30–5.16 (2H,
m, OCH2CH2]CH), 5.04–4.98 (2H, m, CHCH2CH2]CH), 4.58 (2H, d,
J¼3.7 Hz, OCH2CH2]CH), 4.56 (2H, br, CH2OH), 3.91–3.75 (1H, br,
CHN), 3.56 (2H, br, CH2OH), 3.31–3.13 (2H, m, CH2N), 2.30–2.21 (2H,
m, CHCH2CH]CH2), 1.77–1.66 (2H, m, OCH2CH2CH2N), 1.59–1.48
(2H, m, CH3CH2), 0.85 (3H, t, J¼7.4 Hz, CH3CH2); 13C NMR (75 MHz)
4.4.35. Allyl 3-hydroxybutylcarbamate (28a)
Yield 71%; colourless oil; 1H NMR (400 MHz)
d 5.98–5.85 (1H, m,
d
157.8, 135.2, 132.9, 117.4, 117.1, 66.1, 60.2, 59.0, 40.7, 38.0, 32.4, 26.1,
CH]CH2), 5.30 (1H, dd, J¼2.0, 22.9 Hz, CH2]CH), 5.21 (1H, dd,
J¼1.7, 13.9 Hz, CH2]CH), 5.08 (1H, br, NH), 4.56 (2H, d, J¼7.4 Hz,
CH2–CH]CH2), 3.90–3.84 (1H, m, CH), 3.52–3.47 (1H, m, NCH2),
3.22–3.15 (1H, m, CH2N), 1.69–1.51 (2H, m, CHCH2CH3), 1.21 (3H, d,
11.2; IR (neat) 3435, 2965, 2932, 2875, 1672, 1059, 916, 733 cmꢀ1
;
MS (EI, m/z) 242 (MþH)þ, 200 (MꢀCH2CH]CH2, base peak), 156
(68), 142 (48%), 112 (48%), 72 (42%); HRMS calcd for C13H22O3N
240.1594 (MꢀH)þ, found 240.1588.
J¼6.6 Hz, CHCH3); 13C NMR (75 MHz)
d 157.0, 132.7, 117.3, 65.3, 65.1,
38.6, 37.8, 23.1; IR (neat) 3420, 2965, 2932, 2874,1694 cmꢀ1; MS (EI,
m/z) 174 (MþH)þ, 156 (24%), 114 (36%), 88 (52%), 58 (base peak);
HRMS m/z calcd for C8H15O3N (M)þ 173.1046, found 173.1042.
4.4.30. Benzyl hex-5-en-3-yl(3-hydroxypropyl)carbamate (22b)
Yield 63%; colourless oil; 1H NMR (400 MHz)
d 7.36 (5H, m, Ar),
5.69–5.62 (1H, m, CH2]CH), 5.15 (2H, s, CH2Ph), 5.00 (1H, d, J¼7.9
Hz, CH2]CH), 4.97 (1H, s, CH2]CH), 3.94–3.81 (1H, m, NCH), 3.61
(2H, t, J¼5.7 Hz, CH2O), 3.36–3.19 (2H, m, CH2N), 2.29–2.24 (2H, m,
CH2CH]CH2), 1.76–1.69 (1H, m, OCH2CH2CH2N), 1.59–1.50 (2H, m,
4.4.36. trans-3-Allyloxycarbonyl-2-ethyl-6-methyl-1,3-
oxazinane (28b)
Yield 76%; colourless oil; 1H NMR (400 MHz)
d 5.96–5.90 (1H, m,
CH3CH2), 0.85 (3H, t, J¼7.4 Hz, CH3CH2); 13C NMR (75 MHz)
d
158.1,
CH2]CH), 5.56 (1H, br, OCHN), 5.31–5.18 (2H, m, CH2]CH), 4.59
(2H, d, J¼4.2 Hz, CH2CH]CH2), 4.14–4.08 (1H, m, CH2O), 3.96–3.91
(1H, m, CH3–CH), 3.13–3.15 (1H, m, CH2O), 1.98–1.94 (1H, m, CH2–
CH3), 1.79 (1H, br, CH2–CH3), 1.52–1.46 (2H, m, CH–CH2–CH2), 1.16
(3H, d, J¼4.9 Hz, CH3CH), 0.90 (3H, t, J¼5.9 Hz, CH3–CH2); 13C NMR
136.6, 135.2, 128.5, 128.1, 128.0, 127.8, 117.2, 67.4, 60.4, 59.0, 40.7,
38.0, 32.4, 26.1, 11.2; IR (neat) 3428, 2965, 2934, 2876, 1693, 1643,
1454, 1418, 1344, 1057, 698 cmꢀ1; MS (EI, m/z) 292 (Mþ1)þ, 250
(MꢀCH2CH]CH2, 26%), 206 (40%), 91 (base peak); HRMS for
C18H20O3N 250.1438 (MꢀCH2CH]CH2)þ, found 250.1436.
(125 MHz) d 154.4, 133.0, 117.3, 83.1, 66.0, 64.3, 37.2, 32.6, 22.0, 21.8,
9.4; IR (neat) 2972, 2936, 2878, 1697, 766 cmꢀ1; MS (EI, m/z) 214
(MþH)þ, 184 (base peak), 98 (48%), 70 (28%); HRMS m/z calcd for
C11H20O3N (MþH)þ 214.1438, found 214.1446.
4.4.31. tert-Butyl hex-5-en-3-yl(3-hydroxypropyl)carbamate (23b)
Yield 66%; colourless oil; 1H NMR (300 MHz)
d 5.76–5.67 (1H, m,
CH2]CH), 5.06–5.00 (2H, m, CH2]CH), 4.02–3.91 (1H, br, CH), 3.57
(2H, br, CH2O), 3.31–3.15 (2H, br, CH2N), 2.28–2.21 (2H, m,
CH2CH]CH2), 1.78–1.66 (2H, m, CH2CH2CH2), 1.65–1.55 (2H, m,
CH3CH2),1.45 (9H, s, C(CH3)3), 0.87 (3H, t, J¼7.4 Hz, CH3CH2); 13C NMR
4.4.37. Allyl hex-5-en-3-yl(3-hydroxybutyl)carbamate (28c)
(mixture of isomers)
Yield 74%; colourless oil; 1H NMR (400 MHz)
d 5.94–5.88 (1H, m,
(100 MHz)
d
157.6, 135.5, 116.9, 80.1, 59.6, 58.8, 40.6, 38.1, 32.4, 28.4,
OCH2CH2]CH), 5.76–5.63 (1H, m, CHCH2CH2]CH), 5.31–5.19 (2H,
m, OCH2CH2]CH), 5.05–4.99 (2H, m, CHCH2CH2]CH), 4.58 (2H, br
d, J¼4.9 Hz, OCH2CH2]CH), 4.92–3.56 (3H, m), 3.19–3.00 (1H, m),
26.3, 11.3; IR (neat) 3429, 2968, 2932, 2876, 1694, 1366, 1165 cmꢀ1
;
MS (EI, m/z) 258 (MþH)þ, 216 (MꢀCH2CH]CH2, 6%),116 (base peak),

7858
R.W. Bates et al. / Tetrahedron 65 (2009) 7852–7858
111, 3475; Denmark, S. G.; Willson, T. M.; Almstead, N. G. J. Am. Chem. Soc. 1989,
111, 9258; Denmark, S. G.; Almstead, N. G. J. Am. Chem. Soc. 1991, 113, 8089;
Denmark, S. G.; Almstead, N. G. J. Org. Chem. 1991, 56, 6458; Alexakis, A.;
Mangeney, P. Tetrahedron: Asymmetry 1990, 1, 477.
2.30–2.23 (2H, m, CHCH2CH]CH2), 1.70–1.43 (2H, m), 0.91–0.83
(3H, m, CH3CH2).
2. Amat, M.; Escolano, C.; Gomez-Esque, A.; Lozano, O.; Llor, N.; Griera, R.; Molins,
E.; Bosch, J. Tetrahedron: Asymmetry 2006, 17, 1581; Huang, P.-Q. Synlett 2006,
1133; Kinderman, S. S.; de Gelder, R.; van Maarseveen, J. H.; Schoemaker, H. E.;
Hiemstra, H.; Rutjes, F. P. J. T. J. Am. Chem. Soc. 2004, 126, 4100; Maldaner, A. O.;
Pilli, R. A. Synlett 2004, 1343; Botman, P. N. M.; Dommerholt, F. J.; de Gelder, R.;
Broxterman, Q. B.; Schoemaker, H. E.; Rutjes, F. P. J. T.; Blaauw, R. H. Org. Lett.
2004, 6, 4941; Chevallier, F.; Beaudet, I.; Le Grognec, E.; Toupet, L.; Quintard,
J.-P. Tetrahedron Lett. 2004, 45, 761; Fleming, J. J.; Fiori, K. W.; Du Bois, J. J. Am.
Chem. Soc. 2003, 125, 2028; Amat, M.; Llor, N.; Hidalgo, J.; Escolano, C.; Bosch,
J. J. Org. Chem. 2003, 68, 1919; Ito, T.; Yamazaki, N.; Kibayashi, C. Org. Lett.
2002, 4, 2469; Ito, T.; Yamazaki, N.; Kibayashi, C. Synlett 2001, 1506; Peroche,
S.; Remuson, R.; Gelas-Mialhe, Y.; Gramain, J.-C. Tetrahedron Lett. 2001, 42,
4617; Yamazaki, N.; Itoh, T.; Kibayashi, C. Org. Lett. 2000, 2, 465; Sugiura, M.;
Kobayashi, S. Org. Lett. 2001, 3, 477; Agami, C.; Couty, F.; Rabasso, N. Tetra-
hedron 2001, 57, 5393; Yamazaki, N.; Ito, T.; Kibayashi, C. Tetrahedron Lett.
1999, 40, 739; Agami, C.; Couty, F.; Lam, H.; Mathieu, H. Tetrahedron 1998, 54,
8783; Amat, M.; Llor, N.; Bosch, J.; Solans, X. Tetrahedron 1997, 53, 719; Ya-
mazaki, N.; Suzuki, H.; Aoyagi, S.; Kibayashi, C. Tetrahedron 1996, 37, 6161; For
semi-cyclic N,O-acetals, see: Sugiura, M.; Hagio, H.; Hirabayashi, R.; Kobayashi,
S. J. Am. Chem. Soc. 2001, 113, 12510; For a preliminary report of this work,
see: Bates, R. W.; Boonsombat, J.; Lu, Y.; Nemeth, J. A.; Sa-Ei, K.; Song, P.; Cai,
M. P.; Cranwell, P. B.; Winbush, S. Pure Appl. Chem. 2008, 80, 681.
3. For instance: Roulland, E.; Cecchin, F.; Husson, H.-P. J. Org. Chem. 2005, 70,
4474; Blanchet, J.; Bonin, M.; Chiaroni, A.; Micouin, L.; Riche, C.; Husson, H.-P.
Tetrahedron Lett. 1999, 40, 2935; See also Poerwono, H.; Higashiyama, K.; Ta-
kahashi, H. J. Org. Chem. 1998, 63, 2711; Yamazaki, N.; Suzuki, H.; Kibayashi, C.
J. Org. Chem. 1997, 62, 8280.
4.4.38. N-(4-Hydroxybutan-2-yl)-p-toluenesulfonamide (29a)
Yield 68%; colourless solid; mp 58–59 ꢁC; 1H NMR (300 MHz)
d
7.77 (2H, d, J¼8.1 Hz, Ar), 7.29 (2H, d, J¼8.1 Hz, Ar), 4.74 (1H, d,
J¼8.2 Hz, NH), 3.89–3.81 (1H, m, CH), 3.66–3.49 (2H, m, CH2O), 2.43
(3H, s, ArCH3), 2.18 (1H, t, J¼5.2 Hz, OH), 1.76–1.65 (1H, m, NCH–
CH2–CH2O), 1.51–1.42 (1H, m, NCH–CH2–CH2O), 1.00 (3H, d, J¼6.6
Hz, CH3–CH); 13C NMR (125 MHz)
d 143.4, 137.8, 129.7, 127.0, 59.1,
47.5, 39.4, 21.7, 21.5; IR (Nujol) 3171, 1317, 918, 665 cmꢀ1; MS (EI,
m/z) 244 (MþH)þ, 198 (base peak), 155 (74%), 91 (59%); HRMS m/z
calcd for C11H17O3NS (M)þ 243.0924, found 243.0925.
4.4.39. cis-2-Ethyl-4-methyl-3-tosyl-1,3-oxazinane (29b)
Yield 86%; colourless solid; mp 115–116 ꢁC; 1H NMR (400 MHz)
d
7.76 (2H, d, J¼8.1 Hz, Ar), 7.29 (2H, d, J¼8.1 Hz, Ar), 5.36 (1H, t,
J¼7.2 Hz, OCHN), 4.02–3.96 (1H, m, CH2O), 3.86 (1H, dt, J¼3.1, 11.4
Hz, CH2O), 3.79–3.74 (1H, m, CH–CH3), 3.45–3.41 (1H, m, CH2N),
2.41 (3H, s, ArCH3), 2.04–1.90 (2H, m, CH2–CH3), 1.52–1.40 (1H, m,
CH–CH2–CH2), 1.43 (3H, d, J¼7.1 Hz, CH3–CH), 1.18 (1H, dd, J¼2.8,
13.6 Hz, CH–CH2–CH2), 0.99 (3H, d, J¼7.4 Hz, CH3–CH2); 13C NMR
(100 MHz)
d 143.2, 137.6, 129.6, 127.2, 84.9, 55.6, 46.5, 28.0, 27.9,
22.8, 21.5, 10.2; IR (Nujol) 1331, 1155, 814, 667 cmꢀ1; MS (EI, m/z)
284 (MþH)þ, 254 (base peak), 173 (26%), 155 (43%), 91 (41%); HRMS
m/z calcd for C14H20O3NS (MþH)þ 282.1158, found 282.1155.
4. Yazici, A.; Pyne, S. G. Synthesis 2009, 339; Yazici, A.; Pyne, S. G. Synthesis 2009,
513; Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56, 3817.
5. Hollis, K. T.; Robinson, N. P.; Whelan, J.; Bosnich, B. Tetrahedron Lett. 1993, 34,
4309.
6. Cimino, G.; Gavagnin, M.; Sodano, G.; Spinella, A.; Strazzullo, G. J. Org. Chem.
1987, 52, 2301.
7. Bartoli, G.; Cimarelli, C.; Marcantoni, E.; Palmieri, G.; Petrini, M. J. Org. Chem.
1994, 59, 5328.
8. A similar axial preference for substituents near to an N-sulfonyl group has been
observed: Hedley, S. J.; Moran, W. J.; Prenzel, A. H. G. P.; Price, D. A.; Harrity, J. P. A.
Synlett 2001, 1596; The corresponding effect in N-acyl piperidines has been re-
ported: Neipp, C. E.; Martin, S. F. Tetrahedron Lett. 2002, 43, 1779.
9. In contrast, the analogous acetals derived from 3-amino-1-phenylpropanol
yielded cinnamyl amine derivatives due to heterolysis of the benzylic C–O
bond.
4.4.40. N-(Hex-5-en-3-yl)-N-(1-methyl-3-hydroxypropyl)-p-
toluenesulfonamide (29c) (mixture of isomers)
Yield 82%; colourless oil; 1H NMR (400 MHz)
d 7.76–7.74 (4H, m,
Ar), 7.29–7.27 (4H, m, Ar), 5.75–5.66 (1H, m, CH2]CH), 5.60–5.53
(1H, m, CH2]CH), 5.09–4.95 (3H, m, CH2]CH), 3.89–3.87 (1H, m),
3.85–3.77 (2H, m), 3.60–3.54 (1.5H, m), 3.12–3.09 (1.5H, m), 2.53–
2.49 (2H, m), 2.42 (6H, s, ArCH3), 2.34–2.30 (1H, m), 1.86–1.60 (6H,
m), 1.18–1.13 (4.5H, m), 0.89 (1.6H, t, J¼7.4 Hz, CH3CH2), 0.77 (3H, t,
J¼7.4 Hz, CH3CH2).
10. Gandon, L. A.; Russell, A. G.; Gu¨ veli, T.; Brodwolf, A. E.; Kariuki, B. M.; Spencer,
N.; Snaith, J. S. J. Org. Chem. 2006, 71, 5198.
11. Nedolya, N. A.; Dymchenko, V. I.; Afonin, A. V. Zh. Org. Khim. 1994, 30, 507.
12. Ohno, H.; Miyamura, K.; Tanaka, T. J. Org. Chem. 2002, 67, 1359.
13. Xu, G.; Micklatcher, M.; Silvestri, M. A.; Hartman, T. L.; Burrier, J.; Osterling, M.
C.; Wargo, H.; Turpin, J. A.; Buckheit, R. W., Jr.; Cushman, M. J. Med. Chem. 2001,
44, 4092.
14. Gellerman, G.; Elgavi, A.; Salitra, Y.; Kramer, M. J. Pept. Res. 2001, 57, 277.
15. Lee, H. H.; Palmer, B. D.; Baguley, B. C.; Chin, M.; McFadyen, W. D.; Wickham, G.;
Deborah, T.-P.; Wakelin, L. P. G.; Denny, W. A. J. Med. Chem. 1992, 35, 2983.
16. Mattingly, P. G. Synthesis 1990, 366.
Acknowledgements
We thank Nanyang Technological University and the Singapore
Ministry of Education Academic Research Fund Tier 2 (grant
T206B1220RS) for support of this work.
References and notes
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Chem. Soc. 1983, 105, 2904; Denmark, S. E.; Willson, T. M. J. Am. Chem. Soc. 1989,