Aza-Wittig rearrangement of N,N-dipropargylic α-amino alkyllithiums: Periselectivity and steric course

Article abstract of DOI:10.1055/s-2004-830854

The aza-Wittig rearrangement of enantio-defined N,N-dipropargylic α-amino alkyllithiums, generated by tin-lithium exchange, are shown to afford [1,2]- and/or [2,3]-rearrangement products. Both aza-Wittig rearrangements proceed predominantly with inversion of configuration at the Li-bearing carbon terminus.

Full text of DOI:10.1055/s-2004-830854

LETTER
1925
Aza-Wittig Rearrangement of N,N-Dipropargylic a-Amino Alkyllithiums:
Periselectivity and Steric Course
A
za-WittigRea
a
rrangemen
k
t
of
N
,
N
-Dipr
a
opargylic
a
h
-Amino Alk
i
yllithiu
r
ms o Tomoyasu, Katsuhiko Tomooka*
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, Meguro-ku,
Tokyo 152-8552, Japan
Fax +81(3)57343931; E-mail: ktomooka@apc.titech.ac.jp
Received 15 May 2004
N
Abstract: The aza-Wittig rearrangement of enantio-defined N,N-
R'
R'
dipropargylic a-amino alkyllithiums, generated by tin-lithium
exchange, are shown to afford [1,2]- and/or [2,3]-rearrangement
products. Both aza-Wittig rearrangements proceed predominantly
with inversion of configuration at the Li-bearing carbon terminus.
R
SnBu3
1
NH
R'
[1,2]
2
1'
R'
n-BuLi
R
*
1'
2'
Key words: asymmetric, amines, carbanions, Wittig rearrange-
ments, periselectivity
3
3'
N
R'
R
2
Li
NH
[2,3]
2
2
The nitrogen analog of the Wittig rearrangement is an
isomerization of a-metalated tertiary amines to skeletally
rearranged metal amides, which yield secondary
amines.1,2 In general, the aza-Wittig rearrangement is less
facile than the corresponding original (oxa-) Wittig rear-
rangement; however, it is a potentially useful reaction in
3'
R'
•
R
*
R'
4
Scheme 2
terms of synthesis of various kinds of nitrogen-containing periselectivity and steric course (inversion vs. retention)
compounds. Similarly to the original Wittig rearrange- of the aza-Wittig rearrangements.
ment, the problem of competition of the [1,2]- and [2,3]-
shift arises in the rearrangement of an allyl amine system.
As part of our program on the study of a-amino carbanion
chemistry, we have recently reported that the aza-Wittig
rearrangement of the enantio-defined N,N-diallyl-a-ami-
no alkyllithiums, generated by tin-lithium exchange of
enantio-defined a-amino alkylstannanes, proceeds pre-
dominantly with inversion of configuration at the lithium-
bearing carbon terminus, albeit the periselectivity ([1,2]
vs. [2,3]) was not clear (Scheme 1).3–5
At the outset, we examined the periselectivity of the aza-
Wittig rearrangement of the N,N-dipropargylic a-amino
alkyllithiums (R)-2a–c, generated by tin-lithium ex-
change of the N,N-dipropargylic a-amino alkylstannanes
(R)-1a–c. The requisite enantio-defined N,N-dipropar-
gylic a-amino alkylstannanes (R)-1a–c were successfully
prepared from (R)-a-phthalimido alkylstannane3 via reac-
tion with hydrazine hydrate followed by bis-alkynylation
of the free a-amino alkylstannane (>95% ee,
Scheme 3).6,7
The aza-Wittig rearrangement was carried out under the
standard conditions [n-BuLi (5 equiv), THF, –78 to 0 °C,
Table 1].8 The reaction of (R)-1a (R¢ = H) was found to
[1,2]
and/or
[2,3]
1'
1
2'
N
NH
n-BuLi
N
3'
Inv.
R
SnBu3
R
R
Li
2
48% ee
R=PhCH2CH2
>95% ee
NH2
NH2NH2·H2O
Scheme 1
R
SnBu3
O
O
EtOH
80 °C
N
To clarify the steric course of aza-[1,2]- and [2,3]-Wittig
rearrangement separately, we have investigated the rear-
rangements of the enantio-defined N,N-dipropargylic a-
amino alkyllithiums which will provide the different
amines 3 and 4 as the [1,2]- and [2,3]-shift products, re-
spectively (Scheme 2). Disclosed herein are the clear-cut
results of our study of the propargylic version in terms of
>95% ee
R
SnBu3
R=PhCH2CH2
R'C≡CCH2Br
NaH
N
R'
R'
DMF
r.t.
Ph
SnBu3
Yield (2 steps)
(R)-1a (R'=H)
(R)-1b (R'=Me)
(R)-1c (R'=Et)
32%
66%
92%
SYNLETT 2004, No. 11, pp 1925–1928
0
6
.0
9
.2
0
0
4
Advanced online publication: 28.07.2004
DOI: 10.1055/s-2004-830854; Art ID: U14004ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 3

1926
T. Tomoyasu, K. Tomooka
LETTER
give the homopropargylamine 3a ([1,2]-product) as the stereochemistry of 3c was determined as R-configuration
sole product in 75% yield.9 It appears likely that the [2,3]- by the HPLC comparison14 of their urea derivative 8
shift in this rearrangement would be disfavored by an (Scheme 4) with an authentic sample of (R,S)-8, which
electronic repulsion between the migrating terminus and was prepared from (S)-a-oxy alkylstannane (>95% ee)3 as
the alkynyl anion.
shown in Scheme 5.15 Since tin-lithium exchange usually
occurs with retention,16 it appears that the aza-[1,2]-Wit-
tig rearrangement of 1c occurs predominantly with inver-
sion at the Li-bearing carbon terminus.
In sharp contrast, the reaction of (R)-1b (R¢ = Me) afford-
ed the homoallenylamine 4b ([2,3]-product) as the major
product in 25% yield, together with 24% yield of the
destannylated product 5b and a trace amount of [1,2]-shift
product 3b. On the other hand, a similar rearrangement of
(R)-1c (R¢ = Et) afforded a mixture of [1,2]-product 3c
(10%) and [2,3]-product 4c (36%), along with a trace
amount of destannylated product 5c and allene 6c
(15%).10 These results reveal that the periselectivity of
propargylic aza-Wittig rearrangement highly depends on
the substituents at the acetylenic terminus. Similar behav-
ior was previously observed in the rearrangement of the
oxa-analogue.11
OCN
(96% ee, S)
Ph
N
NH
Et
[1,2]
Et
Et
R
SnBu3
R
R
(R)-1c
R=PhCH2CH2
3c (62% ee)
O
O
S
S
n-C5H11
Pd-C, H2
N
N
H
Ph
N
N
Ph
Et
H
Et
Ph
n-C5H11
R
R
S
8
Next, our attention was focused on the steric course of
the aza-Wittig rearrangements. The enantiomeric purity
of rearrangement products 3a, 3c, 4b and 4c was deter-
mined by HPLC analysis of (S)-methylbenzyl urea deriv-
atives (Table 1).12 Surprisingly enough, 3a is racemic,
although 3c, 4b and 4c are optically active. This result
clearly shows that the stereochemical course of propargyl-
ic aza-[1,2]-Wittig rearrangement is strongly affected by
a substituent at the acetylenic terminus.13 The absolute
7
major dr (81%): tR=12.3 min
minor dr (19%): tR=14.3 min
Scheme 4
In the similar way, treatment of the [2,3]-shifted product
4b with (S)-methylbenzyl isocyanate followed by hydro-
genolysis afforded urea 10 as a mixture of four stereoiso-
mers (Scheme 6). All four requisite authentic samples
Table 1 The aza-Wittig Rearrangement of 1a–c
[1,2]
NH
R'
NH
R'
+
R'
R'
R'
R
R
(S)-3 (Ret.)
(R)-3 (Inv.)
n-BuLi
N
(R)-1a–c
THF
–78→0 °C
R'
R
Li
NH
NH
·
[2,3]
(R)-2a (R'=Li)
(R)-2b (R'=Me)
(R)-2c (R'=Et)
+
R'
·
R
R
R'
R'
R=PhCH2CH2
(S)-4 (Ret.)
(R)-4 (Inv.)
N
NH
R'
R'
R'
·
R'
R
R
5
6
Substrate
Products % yielda [% ee]b
Periselectivity
[1,2]:[2,3]
3
4
5
6
(R)-1a (R¢ = H)
(R)-1b (R¢ = Me)
(R)-1c (R¢ = Et)
a Isolated yield.
75 [0]
Trace
10 [62 (R)]
–
–
–
>95:<5
25 [48 (R)]
24
–
<5:>95
36 [66]c
Trace
15d
22:78 (41:59)e
b Determined by HPLC analysis (Chiralcel OD-H) of (S)-methylbenzyl urea derivatives.
c Absolute stereochemistry has not been determined yet.
d A 1:3 mixture of diastereomers; stereochemistry was not determined yet.
e Compound 6c as combined as a [1,2]-shift product.
Synlett 2004, No. 11, 1925–1928 © Thieme Stuttgart · New York

LETTER
Aza-Wittig Rearrangement of N,N-Dipropargylic a-Amino Alkyllithiums
1927
O
NH
H
R'=Li
OH
1. n-BuLi, n-C5H11
I
1. Ts2O, Et3N
i-Pr2N
O
R
R
2. DIBAL-H
R
S
n-C5H11
n-C5H11
2. n-C5H11NH2
R
S
SnBu3
N
[1,2] (Rac.)
>95% ee
R=PhCH2CH2
R'
O
R
Li
S
NH
R'
NH
n-C5H11
OCN
(96% ee, S)
Ph
+
NH
N
N
H
Ph
R'=alkyl
•
R
R
n-C5H11
Ph
n-C5H11
R
R
[1,2] (Inv.)
[2,3] (Inv.)
R'
28% ee
(R, S)-8 tR=14.3 min
Scheme 8
Scheme 5
In summary, we have demonstrated that the aza-Wittig
rearrangement of enantio-defined N,N-dipropargylic a-
amino alkyllithiums proceeds by competitive [1,2]- and
[2,3]-rearrangement pathways, that both aza-Wittig
rearrangements proceed predominantly with inversion of
configuration at the carbanion center. Synthetic applica-
tion of the present aza-Wittig rearrangement is under way.
were separately prepared from stereochemically defined
isoleucines via reduction, Wittig olefination, and hydro-
genation (Scheme 7). By HPLC comparison of a mixture
of 10 with four authentic samples, the absolute configura-
tion of the major isomer of 4b was assigned as R.14 This
stereochemical outcome provides conclusive proof that
the propargylic aza-[2,3]-Wittig rearrangement also pro-
ceeds predominantly with inversion of configuration at
the Li-bearing carbon terminus.
Acknowledgment
This research was supported in part by a Grant-in-Aid for Scientific
Research on Priority Areas (A) ‘Exploitation of Multi-Element
Cyclic Molecules’, Basic Area (B) No. 14350473 and The 21st
Century COE Program ‘Creation of Molecular Diversity and
Development of Functionalities’ from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
OCN
(96% ee, S)
Ph
NH
N
[2,3]
·
R
R
R
SnBu3
4b (48% ee)
(R)-1b
R=PhCH2CH2
References
O
O
S
(1) Reviews: (a) Vogel, C. Synthesis 1997, 497. (b) Tomooka,
K. In The Chemistry of Organolithium Compounds;
Rappoport, Z.; Marek, I., Eds.; Wiley: New York, 2004,
Chap. 12.
n-C4H9
S
N
N
Ph
Pd-C, H2
N
N
H
.
Ph
H
R
R
(2) For recent examples of synthetic applications of the aza-
Wittig rearrangement, see: (a) Broka, C. A.; Shen, T. J. Am.
Chem. Soc. 1989, 111, 2981. (b) Coldham, I. J. Chem. Soc.,
Perkin Trans. 1 1993, 1275. (c) Åhman, J.; Somfai, P.
Tetrahedron Lett. 1996, 37, 2495. (d) Anderson, J. C.;
Whiting, M. J. Org. Chem. 2003, 68, 6160.
9
10
t =17.7 min
dr-1 (26%):
dr-2 (20%):
dr-3 (50%):
dr-4 (4%):
R
tR=19.5 min
t =20.1 min
R
tR=21.0 min
Scheme 6
(3) Tomoyasu, T.; Tomooka, K.; Nakai, T. Tetrahedron Lett.
2003, 44, 1239.
(4) We have also reported that the rearrangement of N,N-
dicrotyl a-amino alkyllithium afforded a mixture of aza-
[1,2]- and [2,3]-Wittig rearrangement product, see ref.3
1. Cbz-Cl, NaOH
2. MeONHMe, Et3N,
i-BuOCOCl
1. (EtO)2P(O)CH2Ph,
NaN(TMS)2
2. n-C4H9Br, NaH
Cbz
NH2
HN
O
O
3. LiAlH4
OH
H
Isoleucines
N
NH
NH
n-BuLi
O
+
S
n-C4H9
Cbz
R
SnBu3
n-C4H9
THF
–78→0 °C
R
R
1. Pd-C, H2
N
N
2
N
Ph
H
2. (S)-Methylbenzyl
isocyanate
3'
[1,2]: 34%
[2,3]: 45%
Ph
Ph
Scheme 9
→ (2R, 3'R)-10
→ (2S, 3'S)-10
→ (2R, 3'S)-10
→ (2S, 3'R)-10
tR=17.4 min
tR=19.0 min
tR=19.9 min
tR=20.5 min
L-allo-Isoleucine
D-allo-Isoleucine
L-Isoleucine
(5) Gawley’s group has reported the first experimental evidence
for the inversion course in the aza-[2,3]-Wittig
D-Isoleucine
rearrangement of (S)-N-allyl-2-lithiopyrrolidine, which
considerably competes with the [1,2]-Wittig rearrangement
process. However, no systematic study has been made on the
steric course at the Li-bearing terminus of the aza-[1,2]-
Wittig rearrangement. See: Gawley, R. E.; Zhang, Q.;
Campagna, S. J. Am. Chem. Soc. 1995, 117, 11817.
Scheme 7
The observed stereochemical outcomes are summarized
in Scheme 8.
Synlett 2004, No. 11, 1925–1928 © Thieme Stuttgart · New York

1928
T. Tomoyasu, K. Tomooka
LETTER
7.14–7.30 (m, 5 H). 13C NMR (CDCl3): d = 3.5, 13.8, 32.3,
35.3, 36.1, 59.7, 74.4, 74.6, 77.3, 98.3, 125.7, 128.3, 128.4,
142.2, 206.8. HRMS [(S)-methylbenzyl urea derivative 9,
EI]: m/z calcd for C26H30N2O: 386.2358. Found: 386.2350.
Compound 4c: 1H NMR (CDCl3): d = 1.04 (t, J = 7.4 Hz, 3
H), 1.11 (t, J = 7.4 Hz, 3 H), 1.77–1.98 (m, 4 H), 2.13–2.22
(m, 2 H), 2.65 (t, J = 7.9 Hz, 2 H), 3.24 (t, J = 6.4 Hz, 1 H),
3.33 (tq, J = 2.3, 16.2 Hz, 2 H), 4.81 (dt, J = 1.3, 3.8 Hz, 2
H), 7.14–7.30 (m, 5 H). 13C NMR (CDCl3): d = 12.2, 12.4,
14.1, 20.6, 32.4, 35.8, 36.2, 59.3, 77.4, 77.5, 84.8, 105.9,
125.7, 128.3, 128.4, 142.3, 205.8. HRMS [(S)-methylbenzyl
urea derivative, EI]: m/z calcd for C28H34N2O: 414.2671.
Found: 414.2654. Compound 6c (major diastereomer): 1H
NMR (CDCl3): d = 1.05 (t, J = 7.4 Hz, 3 H), 1.11 (t, J = 7.4
Hz, 3 H), 1.75–1.85 (m, 2 H), 1.98–2.12 (m, 2 H), 2.13–2.24
(m, 2 H), 2.61–2.74 (m, 2 H), 3.22–3.52 (m, 3 H), 4.95–5.00
(m, 1 H), 5.27 (dd, J = 1.3, 6.2 Hz, 1 H), 7.18–7.30 (m, 5 H).
13C NMR (CDCl3): d = 12.4, 13.4, 14.1, 22.1, 32.3, 36.3,
37.9, 56.9, 77.4, 84.9, 86.7, 93.9, 125.7, 128.3, 128.5, 142.2,
203.8.
[1,2]
and/or
[2,3]
n-BuLi
N
N
NH
Inv.
SnBu3
Li
48% ee
Scheme 10
(6) For the preparation of N,N-dipropargyl alkylstannane (R)-
1a, N,N-diisopropylethylamine was utilized as a base instead
of NaH.
(7) All the compounds were characterized by 1H NMR and 13
C
NMR. Data for selected products are as follows. (R)-1a: 1H
NMR (CDCl3): d = 0.86–0.94 (m, 15 H), 1.24–1.53 (m, 12
H), 1.80–1.93 (m, 1 H), 2.07–2.20 (m, 1 H), 2.23 (t, J = 2.3
Hz, 2 H), 2.58–2.82 (m, 2 H), 3.17 (dd, J = 9.2, 5.4 Hz, 1 H),
3.26 (dt, J = 6.5, 2.3 Hz, 2 H), 3.55 (dt, J = 6.5, 2.3 Hz, 2 H),
7.17–7.30 (m, 5 H). 13C NMR (CDCl3): d = 11.0, 13.6, 27.6,
29.3, 34.2, 34.7, 42.6, 55.9, 73.1, 80.3, 125.6, 128.3, 128.5,
142.4. [a]D –45.6 (c 0.25, CHCl3). (R)-1b: 1H NMR
(CDCl3): d = 0.86–0.92 (m, 15 H), 1.23–1.50 (m, 12 H), 1.82
(t, J = 2.3 Hz, 6 H), 1.82–1.92 (m, 1 H), 2.02–2.20 (m, 1 H),
2.60–2.87 (m, 2 H), 3.08 (dd, J = 16.2, 2.3 Hz, 2 H), 3.23
(dd, J = 4.5, 10.4 Hz, 1 H), 3.50 (dd, J = 16.2, 2.3 Hz, 2 H),
7.16–7.30 (m, 5 H). 13C NMR (CDCl3): d = 3.8, 10.9, 13.7,
27.6, 29.4, 31.6, 34.6, 43.2, 55.9, 75.6, 80.6, 125.6, 128.2,
128.6, 142.7. [a]D –63.6 (c 0.25, CHCl3). (R)-1c: 1H NMR
(CDCl3): d = 0.86–0.93 (m, 15 H), 1.13 (t, J = 7.4 Hz, 6 H),
1.24–1.53 (m, 12 H), 1.80–1.93 (m, 1 H), 2.07–2.28 (m, 1
H), 2.19 (tq, J = 7.4, 2.1 Hz, 4 H), 2.58–2.70 (m, 1 H), 2.75–
2.86 (m, 1 H), 3.07 (dt, J = 16.2, 2.1 Hz, 2 H), 3.31 (dd,
J = 9.4, 5.4 Hz, 1 H), 3.50 (dt, J = 16.2, 2.1 Hz, 2 H), 7.16–
7.30 (m, 5 H). 13C NMR (CDCl3): d = 10.8, 12.6, 13.6, 13.9,
27.6, 29.4, 34.6, 34.8, 43.3, 55.9, 75.8, 86.5, 125.5, 128.2,
128.5, 142.7. [a]D –65.2 (c 0.25, CHCl3).
(10) The formation of 6c can be explained by two possible
pathways. The first is the conversion of the alkynyl group
into an allenyl group by deprotonation at the propargylic
position of 2c, followed by [1,2]-allenyl migration (path A).
The second is the deprotonation of [1,2]-shifted product
(path B). However, the exact mechanism is unclear at
present.
path A
Li
Et
·
n-BuLi
Et
[1,2]
N
2
1'
Li
R
Li
NLi
N
·
Et
n-BuLi
[1,2]
H
R
R
Li
2c
(8) General Procedure for aza-Wittig Rearrangement: To a
THF (8 mL) solution of (R)-1c (200 mg, 0.36 mmol) was
added n-BuLi (1.13 mL, 1.60 M in hexane, 1.80 mmol)
dropwise at –78 °C. After the addition, the solution was
stirred for 15 min at –78 °C, and the temperature was
allowed to rise to 0 °C over a period of 4 h. The reaction was
quenched with sat. aq NH4Cl and the product was extracted
with Et2O. The combined organic phase was dried over
Na2SO4, filtered and the solvent was removed in vacuo. The
residue was purified by silica gel column chromatography
(hexane–Et2O = 5:1) to give the [1,2]-product 3c (10 mg,
10%), [2,3]-product 4c (35 mg, 36%) and allene 6c (14 mg,
15%).
NLi
Et
path B
R
H
Scheme 11
(11) The periselectivity of the Wittig rearrangement of
propargylic ethers also depends upon the kind of substituents
at the acetylenic terminus, see: Tomooka, K.; Komine, N.;
Nakai, T. Synlett 1997, 1045.
(12) Attempts to separate the enantiomers of rearrangement
products 3 and 4 at this stage using chiral HPLC (OD-H,
AD) failed. Also, attempts to determine the diastereomer
ratio of 7 and 9 using achiral HPLC analysis (ODS) failed.
(13) Non-stereospecificity of the rearrangement of 2a is
understandable if the electronic repulsion between the
radical pairs prevents radical recombination. In that case, the
radical recombination proceeds at a slow rate; thus, the
chiral migrating radical can be racemized during the
reaction.
(14) HPLC analysis was carried out on a Chiralcel OD-H (0.46 ×
25 cm) using heptane:i-PrOH:MeOH = 99.8:0.15:0.05 v/v
(0.5 mL/min) as the mobile phase.
(15) Low enantiopurity of (R,S)-8 is attributed to the
racemization of chiral a-oxy lithium which generated via
Sn–Li exchange.
(9) Data for selected products are as follows. Compound 3a: 1H
NMR (CDCl3) d = 1.80–1.89 (m, 2 H), 2.02 (t, J = 2.6 Hz, 1
H), 2.21 (t, J = 2.6 Hz, 1 H), 2.41 (ddq, J = 16.8, 5.3, 2.6 Hz,
2 H), 2.69 (t, J = 7.9 Hz, 2 H), 2.91–2.98 (m, 1 H), 3.47 (t,
J = 2.6 Hz, 2 H), 7.19–7.31 (m, 5 H). 13C NMR (CDCl3):
d = 23.2, 32.0, 35.3, 35.7, 54.0, 70.5, 71.4, 80.9, 81.9, 125.7,
128.2, 128.2, 141.7. HRMS (EI): m/z calcd for C15H17N:
211.1361. Found: 211.1351. Compound 3c: 1H NMR
(CDCl3): d = 1.12 (t, J = 7.4 Hz, 3 H), 1.13 (t, J = 7.4 Hz, 3
H), 1.77–1.86 (m, 2 H), 2.18 (q, J = 7.4 Hz, 2 H), 2.19 (q,
J = 7.4 Hz, 2 H), 2.20–2.46 (m, 2 H), 2.68 (t, J = 7.9 Hz, 2
H), 2.80–2.90 (m, 1 H), 3.42 (t, J = 2.4 Hz, 2 H), 7.15–7.30
(m, 5 H). 13C NMR (CDCl3): d = 12.4, 12.5, 14.0, 14.3, 23.6,
32.0, 35.4, 36.2, 54.7, 70.8, 75.9, 80.0, 84.0, 125.8, 128.3,
128.4, 142.3. HRMS [(S)-methylbenzyl urea derivative 7,
EI]: m/z calcd for C28H34N2O: 414.2671. Found: 414.2657.
Compound 4b: 1H NMR (CDCl3): d = 1.64 (t, J = 3.1 Hz, 3
H), 1.75–1.87 (m, 2 H), 1.80 (s, 3 H), 2.64 (t, J = 8.1 Hz, 2
H), 3.23 (t, J = 7.1 Hz, 1 H), 3.30 (m, 2 H), 4.68 (m, 2 H),
(16) Retention of stereochemistry in tin-lithium exchange
reactions is well-known for the generation of a-hetero
alkyllithiums, see: Pearson, W. H.; Lindbeck, A. C.; Kampf,
J. W. J. Am. Chem. Soc. 1993, 115, 2622; and references
cited therein.
Synlett 2004, No. 11, 1925–1928 © Thieme Stuttgart · New York