Enantioselective syntheses and X-ray structures of (S)- and (R)-N-norlaudanidine: trace opium constituents

Article abstract of DOI:10.1016/j.tetlet.2009.10.114

The enantioselective synthesis of each of the enantiomers of N-norlaudanidine, a minor Papaver somniferum opium benzyltetrahydoisoquinoline alkaloid is described. This was achieved using a chiral auxiliary-mediated Bischler-Napieralski cyclization-sodium borohydride reduction strategy. The X-ray crystal structures of each of these secondary amines are reported.

Full text of DOI:10.1016/j.tetlet.2009.10.114

Tetrahedron Letters 51 (2010) 177–180
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective syntheses and X-ray structures of (S)- and
(R)-N-norlaudanidine: trace opium constituents
*
Ahmed L. Zein, Otman O. Dakhil, Louise N. Dawe, Paris E. Georghiou
Department of Chemistry, Memorial University of Newfoundland, St. John’s, Newfoundland and Labrador, Canada A1C 2Z1
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective synthesis of each of the enantiomers of N-norlaudanidine, a minor Papaver somnife-
rum opium benzyltetrahydoisoquinoline alkaloid is described. This was achieved using a chiral auxiliary-
mediated Bischler–Napieralski cyclization-sodium borohydride reduction strategy. The X-ray crystal
structures of each of these secondary amines are reported.
Received 16 October 2009
Accepted 23 October 2009
Available online 1 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Benzyltetrahydoisoquinolines
Enantioselective synthesis
N-Norlaudanidine
Laudanine
Palaudine
Heroin
Opium
Papaver somniferum
X-ray crystallography
1. Introduction
knowledge, no previous unambiguous direct assignment of these
particular compounds has been reported.
Benzyltetrahydroisoquinolines (‘BTHIQ’) which contain a B ring
that is reduced at the C1–C2 and C3–C4 positions are known to be
key biosynthetic precursors to many naturally occurring alkaloids.
These include morphine and codeine which are found in, or are de-
rived from, the opium poppy Papaver somniferum.1–5 The global
problem of narcotics abuse, especially involving heroin (1) and ille-
gal opium poppy cultivation and processing, has prompted re-
newed research into the analytical chemistry of heroin5,6 which
also includes the detection and analysis of the minor BTHIQ con-
stituents. Some of these constituents of interest (Fig. 1) include
laudanosine (2), reticuline (3), codamine (4), and laudanine (5).
Laudanine, which is also known as ‘racemic laudanidine’, and ret-
iculine occur in both enantiomeric forms in opium.7 The recent re-
port by Toske et al.,5 which described the GC–MS analysis of
neutral heroin impurities derived from BTHIQs 2–5, piqued our
interest in the application of our synthetic methodology toward
the enantioselective syntheses of 6a and 6b, the (S)- and (R)-enan-
tiomers of N-norlaudanidine (1,2,3,4-tetrahydro-l-(3-hydroxy-4-
methoxybenzyl)-6,7-dimethoxyisoquinoline), respectively, and to
unambiguously assign the chirality of these compounds by their
optical rotations and X-ray crystallography. To the best of our
(ꢀ)-N-Norlaudanine is a component part of the pathway for the
biosynthesis of the benzylisoquinoline alkaloids in Papaver som-
niferum.7 It has been found to be incorporated into palaudine, an-
other minor benzylisoquinoline constituent found in opium.8 The
fact that radiolabelled N-norlaudanine, whose absolute configura-
tion was not defined by Brochmann–Hannssen and co-workers,7
was incorporated into palaudine was an evidence that complete
methylation was not necessary for dehydrogenation to take place
in Papaver somniferum. Herein, we report the enantioselective syn-
theses of (S)- and (R)-N-norlaudanidine (6a) and (6b), respectively,
and also their respective X-ray structures.
2. Results and discussion
The 1960s and 1970s witnessed a great deal of interest and ad-
vances in the chemistry and biogenetic aspects of the BTHIQ alka-
loids due primarily to their significant and important medicinal
and pharmacological activities. The groups of Battersby9 and
Brochmann–Hannssen7 published a series of papers on the biosyn-
thetic pathways of benzylisoquinolines and BTHIQs, in particular
with reference to the opium alkaloids. Many of the structural elu-
cidations were conducted with painstaking degradation studies
and correlations with reference compounds whose absolute con-
figurations were unambiguously defined.10 In many instances,
* Corresponding author. Tel.: +1 709 737 8517.
E-mail address: parisg@mun.ca (P.E. Georghiou).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.114

178
A. L. Zein et al. / Tetrahedron Letters 51 (2010) 177–180
MeO
MeO
MeO
HO
AcO
O
NMe
NMe
H
N
H
OMe
OMe
OH
OMe
( )
Reticuline
Me
AcO
1
2
3
Heroin
(S)-(+)-Laudanosine
MeO
MeO
MeO
MeO
MeO
HO
NMe
NH
NMe
H
OH
OMe
Laudanine
Figure 1. Structures of heroin (1) and some BTHIQ alkaloids.
OH
OMe
(S)-N-Norlaudanidine
OMe
OMe
(S)-(+)-Codamine
6a
4
5
(
)
X-ray crystallographic determinations have been obtained on key
BTHIQs. In most cases, however, in which total syntheses of target
BTHIQs have been reported, the syntheses have yielded only race-
mic mixtures, even though the chirality of a large number of natu-
rally occurring BTHIQs is due to the presence of only a single
stereogenic center at the C-1 position of the tetrahydroisoquino-
line unit. In recent years, however, development of new synthetic
methodologies has enabled enantioselective syntheses of numer-
ous alkaloids in general, including those which have isoquinoline
subunits. A recent example is the enantioselective total synthesis
of (S)-(+)-laudanosine (2) by Mujahidin and Doye, who employed
a combination of a Sonogashira coupling reaction, Petasis’ reagent,
and a Noyori catalyst in their novel approach.11
The enantioselective syntheses of BTHIQ and bisbenzyltetrahy-
droisoquinoline (‘BBIQ’) alkaloids via the Bischler–Napieralski
cyclization reaction in particular have recently been reviewed by
Chrzanowska and Rozwadowska.12a–c We previously employed
the chiral auxiliary (S)-a
-methylbenzylamine13 for the first enan-
tioselective synthesis of (ꢀ)-tejedine14 via a Bischler–Napieralski
cyclization–reduction sequence which has been frequently em-
ployed by others. This is the approach we used in our syntheses
of 6a and 6b which is outlined below.
O
CHO
a
Cl
MeO
MeO
OH
OBn
8
7
MeO
HO
MeO
MeO
O
MeO
MeO
CHO
b
c
NH
CA*
NH
CA*
10a/b
11a/b
d
9
MeO
MeO
NR
MeO
OR1
N
e,f
CA*
O
MeO
OBn
OMe
OMe
6a: R = R1 = H from 6c
6b: R = R1 = H from 6d
6c: R = CA*; R1 = Bn from 12a
6d: R = CA*; R1 = Bn from 12b
12a/b
Scheme 1. Reagents and conditions: (a) (1) BnBr, DMSO, 98%; (2) CBr4, PPh3, CH2Cl2, 93%; (3) pyrrolidine, H2O, rt, 91%; (4) 1.0 M HCl(aq)/dioxane; (5) (COCl)2, benzene, 94%. (b)
*
(1) (CH3)2SO4, K2CO3, acetone, 95%; (2) CBr4, PPh3, CH2Cl2, 92%; (3) pyrrolidine, H2O, rt, 91%; 4. 1.0 M HCl(aq)/dioxane; (5) (COCl)2, benzene, 96%; (6) CA = (S)- or (R)-
a-
methylbenzylamine, 5% NaOH(aq), CH2Cl2, 92%; (c) B2H6, THF, BF3ꢁEt2O, 86%; (d) 8, 5% NaOH(aq), CH2Cl2, 72%; (e) (1) POCl3, benzene; (2) NaBH4, MeOH, 89%, (95% de); (f) H2,
10% Pd/C, EtOH, 10% HCl(aq): 6a or 6b ꢂ72%.

A. L. Zein et al. / Tetrahedron Letters 51 (2010) 177–180
179
Figure 2. 50% probability ellipsoid ORTEP X-ray structure of 6a. Solvent benzene molecule omitted for clarity.
2.1. Synthesis
zylamine in a Bischler–Napieralski cyclization. These free second-
ary amines could be isolated in high yields and for the first time
afforded successful X-ray crystallographic structures and optical
rotations.
The syntheses of both 6a and 6b were accomplished as outlined
in Scheme 1 with the only difference being the choice of the chiral
auxiliary used within the step b: 6a was obtained using (S)-
a-
methylbenzylamine, and 6b with (R)- -methylbenzylamine. The
a
Acknowledgments
benzyl component was synthesized via the intermediate 8 which
was obtained in 78% overall yields15 from 5 steps, starting from
the commercially available 3-hydroxy-4-methoxybenzaldehyde
(isovanillin) (7) which was elongated using the method of Kim
This work was supported by Memorial University of Newfound-
land and the Natural Sciences and Engineering Research Council of
Canada (NSERC); the Government of Egypt (ALZ) and the Govern-
ment of Libya (OOD) are acknowledged for scholarships to A. L.
Zein and O. O. Dakhil.
et al.16 Using (S)-
a-methylbenzylamine as the chiral auxiliary,
intermediate 10a was obtained in 70% overall yields from 6 steps
from vanillin (9). The corresponding 10b was obtained in the same
manner but using (R)-a-methylbenzylamine as the chiral auxiliary.
Supplementary data
Reduction of 10a (or 10b) to the secondary chiral auxiliary-pro-
tected amines 11a (or 11b) was accomplished in 86% yields via
BF3ꢁetherate-mediated reactions with B2H6 in THF. Schotten–Bau-
mann amidation between 11a (or 11b) and 8 formed the amides
12a (or 12b) in 72% yields. Bischler–Napieralski cyclization-NaBH4
reduction of 12a and 12b afforded 6c and 6d, respectively, with
ꢂ95% de, as determined from integrations of the signals at
d = 5.79 ppm (major) and 5.86 ppm in the respective 1H NMR spec-
tra of the major and minor diastereomers in the crude reaction
products. Catalytic hydrogenolysis of 6c and 6d removed the chiral
auxiliary groups with concomitant removal of the benzyl-protect-
ing groups to afford 6a and 6b, respectively, in 70% yields. Crystal-
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.10.114.
References and notes
1. Shamma, M. The Isoquinoline Alkaloids: Chemistry and Pharmacology. In
Blomquist, A. T., Wasserman, H., Eds.; Academic Press: New York, 1972; pp 44–
152.
2. Brochmann-Hanssen, E.; Furuya, T. J. Pharm. Sci. 1964, 53, 575.
3. Brochmann-Hanssen, E.; Nielsen, B. Tetrahedron Lett. 1965, 18, 1271–1274.
4. Brochmann-Hanssen, E.; Nielsen, B.; Utzinger, G. E. J. Pharm. Sci. 1965, 54,
1531–1532.
5. Toske, S. G.; Cooper, S. D.; Morello, D. R.; Hays, P. A.; Casale, J. F.; Casale, E. J.
Forensic Sci. 2006, 51, 308–320.
lization afforded both 6a and 6b in optically pure forms with [
values of +9 and ꢀ9, respectively.
a]
D
6. Lurie, I. S.; Toske, S. G. J. Chromatogr., A 2008, 1188, 322–326.
7. Brochmann-Hanssen, E.; Chen, C.; Chen, C. R.; Chiang, H.; Leung, A. Y.;
McMurtrey, K. J. Chem. Soc., Perkin Trans. 1 1975, 1531–1537.
8. Brochmann-Hanssen, E.; Hirai, K. J. Pharm. Sci. 1968, 57, 940–943.
9. Battersby, A. R.; Binks, R.; Francis, R. J.; McCaldin, D. J.; Ramuz, H. J. Chem. Soc.
1964, 3600–3610. and references cited therein.
10. See, for example: Ferrari, C.; Deulofeu, V. Tetrahedron 1962, 18, 419–425.
11. Mujahidin, D.; Doye, S. Eur. J. Org. Chem. 2005, 2689–2693. and references cited
therein.
12. (a) Chrzanowska, M.; Rozwadowska, M. D. Chem. Rev. 2004, 104, 3341–3370; (b)
Rozwadowska, M. D. Heterocycles 1994, 39, 903; For a recent different approach
to the enantioselective synthesis of some benzyltetrahydroisoquinolines via a
Bischler–Napieralksi approach see: (c) Pyo, M. K.; Lee, D.-H.; Kim, D.-H.; Lee, J.-
H.; Moon, J.-C.; Chang, K. C.; Yun-Choi, H. S. Bioorg. Med. Chem. Lett. 2008, 18,
4110–4114.
2.2. X-ray crystallography
In contrast to reports17 that unprotected secondary amines in
similar compounds are unstable, we were able to crystallize both
enantiomers from benzene and obtain single-crystal X-ray struc-
tures and also determine their optical rotations. Figure 2 shows
6a which, like compounds 2 and 4, is both S and dextrorotatory.
The X-ray structure revealed that a molecule of benzene is present
in the crystal lattice.18
The single-crystal X-ray of 6b had similar X-ray data19 and as
expected, it also contained a molecule of benzene in the crystal
lattice.
13. The use of this chiral auxiliary was first reported by: Okawara, T.; Kametani, T.
Heterocycles 1974, 2, 571–574.
14. Wang, Y.; Georghiou, P. E. Org. Lett. 2002, 4, 2675–2678.
15. Yields in all the steps outlined in Scheme 1 were not optimized. Experimental
details: 1H NMR (500 MHz) and 13C NMR (175 MHz) in CDCl3 (unless otherwise
noted).
3. Conclusions
Compound 10a: To a stirred solution of oxalyl chloride (1.7 ml, 19.2 mmol) in
anhydrous benzene (20 ml) were added 2,3-dimethoxyphenylacetic acid (3.2 g,
16 mmol) in one batch and DMF (1 drop). The reaction mixture was stirred
until the evolution of gas ceased. The benzene was evaporated using a rotary
evaporator to give the crude acid chloride, which was used directly in the next
Both enantiomers of the opium alkaloids, (S)- and (R)-N-norlau-
danidine 6a and 6b, were synthesized in high enantioselectivity,
respectively, using the chiral auxiliaries (S)- and (R)–a-methylben-

180
A. L. Zein et al. / Tetrahedron Letters 51 (2010) 177–180
-methylbenzylamine (2.74 ml, 20.8 mmol)
step. To a stirred mixture of (S)-
a
filtered, and concentrated in vacuo. The residue was purified by preparative-
layer chromatography (30% EtOAc:hexane) to give compound 6c (0.80 g, 75%)
as a colorless oil. 1H NMR: d 7.39–7.13 (m, 10H, Ar-H), 6.73 (d, J = 5 Hz, 1H),
6.58 (s, 1H), 6.48 (d, J = 2.5 Hz, 1H), 6.46 (dd, J = 5 and 2.5 Hz, 1H), 5.79 (s, 1H),
5.00 (AB d, J = 13 Hz, 1H), 4.94 (AB d, J = 13 Hz, 1H), 3.85 (s, 3H), 3.84 (s, 3H),
3.76 (q, J = 8 Hz, 1H), 3.67 (t, J = 10 Hz, 1H), 3.48 (s, 3H), 3.26–3.14 (m, 2H), 3.01
(dd, J = 13 Hz and 2.5 Hz, 1H), 2.90–2.83 (m, 1H), 2.68–2.63 (m, 1H), 2.43 (dd,
J = 10 and 2.5 Hz, 1H), 1.35 (d, J = 10 Hz, 3H); 13C NMR: d 148.34, 148.07,
147.56, 146.98, 146.58, 133.12, 129.96, 128.90, 128.60, 128.18, 127.79, 127.77,
126.98, 126.87, 123.05, 115.99, 111.85, 111.78, 111.57, 71.19, 61.13, 59.61,
56.60, 56.16, 55.90, 42.29, 40.23, 24.45, 23.79; 22.47. APCl-MS (m/z): 524.3
and CH2Cl2/aqueous 5% NaOH (1:1.5, 26.1 ml) was added dropwise a solution
of the above-mentioned crude acid chloride in CH2Cl2 (30 ml) at 0 °C. After
stirring at rt for 1 h, the reaction mixture was extracted with chloroform
(30 ml ꢃ 3), washed with water (20 ml ꢃ 3), dried over anhydrous MgSO4,
filtered, and the solvent was then evaporated. The residue was purified by flash
column chromatography (30% EtOAc/hexane) to afford 10a (4.4 g, 92%) as a
colorless solid, mp 108–110 °C, 1H NMR: d 7.35–7.19 (m, 5H, Ar-H), 6.84–6.75
*
(m, 3H, Ar-H ), 5.65 (d, J = 10 Hz, 1H), 5.17–5.11 (m, 1H), 3.89 (s, 3H), 3.84 (s,
3H), 3.53 (s, 2H), 1.41 (d, J = 5 Hz, 3H); APCl-MS (m/z): 300.1 (M++1, 100).
Compound 10b: The preparation is as given for 10a but with (R)-a-
methylbenzylamine to afford 10b (4.4 g, 92%) as a colorless solid, mp 108–
110 °C.
(M++1, 100). [
a] +20 (c 0.010, MeOH).
D
Compound 6d: The preparation is as given for 6a but with 6b to afford 6d (0.80
Compound 11a: To a solution of 10a (2.1 g, 6.6 mmol) in anhydrous THF
(60 ml) under Ar was added BF3ꢁEt2O (0.41 ml, 3.2 mmol). The mixture was
heated to gentle reflux and B2H6ꢁTHF (18 ml, 18 mmol) was then added
dropwise. The reaction mixture was heated at reflux for 2 h, and then cooled to
0 °C and aqueous 20% HCl (100 ml) was added to the mixture. The reaction
mixture which was stirred at 0 °C for 1 h and then overnight at rt was made
basic to pH 13 with aqueous 50% KOH solution. The mixture was then
extracted with CH2Cl2 (30 ml ꢃ 3). The combined organic layers were washed
with water (20 ml ꢃ 3), dried over anhydrous MgSO4, filtered, and the solvent
was evaporated to afford 11a (1.7 g, 88%) as a viscous oil which was pure
enough to be used directly in the next step without further purification. 1H
NMR: 7.31–7.20 (m, 5H, Ar-H), 6.78 (d, J = 10 Hz, 1H), 6.71 (dd, J = 10 & 2.5 Hz,
1H), 6.67 (d, J = 2.5 Hz, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 3.78–3.74 (q, J = 5 Hz, 1H),
2.76–2.67 (m, 4H), 1.52 (br, 1H), 1.32 (d, J = 10 Hz, 3H); 13C NMR: d 149.29,
147.81, 146.02, 133.04, 128.79, 127.26, 126.93, 121.00, 112.31, 111.68, 58.62,
56.33, 56.32, 49.33, 36.32, 24.71; MS (m/z): 284.2 (M+, 22).Compound 11b: The
preparation is as given for 10a but using 10b to afford 11b (1.6 g, 85%). 1H and
13C NMR spectra and APCI-MS data were identical with 11a.
Compound 12a: To a stirred solution of oxalyl chloride (1.0 ml, 11 mmol) in
anhydrous benzene (20 ml) were added 3-benzyloxy-4-methoxyphenylacetic
acid (derived in 3 steps16 from 7) (2.6 g, 9.6 mmol) in one batch and DMF (10
drops). The reaction mixture was stirred until the evolution of gas ceased. The
benzene was evaporated using a rotary evaporator to give acid chloride 8,
which was used directly in the next step. To a stirred mixture of 11a (2.7 g,
9.6 mmol) and CH2Cl2/aqueous 5% NaOH (1:1.5, 12.8 ml) was added dropwise a
solution of the crude acid chloride in CH2Cl2 at 0 °C. After stirring at rt for 1 h,
the reaction mixture was extracted with chloroform (30 ml ꢃ 3), washed with
water (20 ml ꢃ 3), dried over anhydrous MgSO4, filtered, and the solvent was
then evaporated. The residue was purified by flash column chromatography
(30% EtOAc/hexane) to afford 12a (3.7 g, 72%) as a viscous oil whose NMR
spectra were complex due to the presence of rotamers. APCl-MS (m/z): 540.3
(M++1, 100).
g, 75%) as a colorless oil. ½a D
ꢄ
ꢀ38 (c 0.010, MeOH). 1H and 13C NMR spectra and
APCI-MS data were identical with 6c.
Compound 6a: To a solution of compound 6c (200 mg, 0.38 mmol) in EtOAc
(1.5 ml) and EtOH (4.5 ml) was added aqueous 10% HCl (0.83 ml). The resulting
solution was hydrogenated over 10% Pd/C for 12 h with stirring. Filtration over
Celite followed by evaporation of the solvent afforded a residue, which was
dissolved in water (5 ml) and CH2Cl2 (5 ml), and basified to pH 13 with
saturated NaHCO3. The aqueous layer was then acidified to pH 7 and extracted
with CH2Cl2 (3 20 ml). The combined organic layers were washed with brine,
dried over MgSO4, and concentrated in vacuo to afford a brown oil which was
purified by preparative TLC (silica gel, 30% EtOAc in hexane) to afford 6a
(90 mg, 72%) as a colorless solid, mp 140–141 °C (benzene). 1H NMR: d 6.83 (d,
J = 2.5 Hz, 1H), 6.80 (d, J = 10 Hz, 1H), 6.71 (dd, J = 2.5 and 10 Hz, 1H), 6.62 (s,
1H), 6.59 (s, 1H), 4.17 (dd, J = 5 and 10 Hz, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 3.82 (s,
3H), 3.24–3.19 (m, 1H), 3.12 (d, J = 2.5 Hz, 1H), 3.10 (d, J = 5 Hz, 1H), 2.96–2.91
(m, 1H), 2.86–2.81 (m, 1H), 2.76–27.0 (m, 2H); 13C NMR: d 147.92, 147.46,
146.29, 145.90, 132.39, 130.56, 127.48, 121.19, 115.86, 112.21, 111.28, 109.88,
57.11, 56.37, 56.24, 42.30, 40.80, 29.62; APCl-MS (m/z): 330.1 (M++1, 100).
APCI-MS (m/z): 330.1 (M++1, 100). ½a D
ꢄ
+9 (c 0.010, MeOH).
Compound 6b: The preparation is as given for 6a but with 6d to afford 6b as a
colorless solid, (44 mg, 70%), mp 140–141 °C (benzene). 1H and 13C NMR
spectra and APCI-MS were identical with 6a. APCl-MS (m/z): 330.1 (M++1, 100);
½aꢄD ꢀ9 (c .085, MeOH).
16. Huh, D. H.; Jeong, J. S.; Lee, H. B.; Ryu, H.; Kim, Y. G. Tetrahedron 2002, 58, 9925–
9932.
17. Czarnocki, Z.; Mieczkowski, J. B.; Ziolkowski, M. Tetrahedron: Asymmetry 1996,
7, 2711–2720.
18. X-ray crystallography of 6a (from benzene): orthorhombic, P212121 (no. 19),
a = 8.3887(17), b = 9.865(2), c = 26.407(6), V = 2185.3(8) Å3, Z = 4, qcalcd
=
1.238 g cmꢀ3
data). The intensity data for 6a and 6b were recorded on a Rigaku AFC8-Saturn 70
system equipped with SHINE optic with MoK radiation (k = 0.71070 Å) at
, l rI), wR2 = 0.0921 (for all
= 0.83 cmꢀ1, final R1 = 0.0371 (for I > 2
a
Compound 12b: The preparation is as given for 12a but with 11b to afford 12b
(3.7 g, 72%) as a colorless oil. APCl-MS (m/z): 540.3 (M++1, 100).Compound 6c:
Compound 12a (1.0 g, 1.8 mmol), POCl3 (3.2 ml, 35 mmol), and benzene
(50 ml) were combined under Ar and heated to reflux at 90 °C. After
123(2) K. Compound 6a was solved by direct methods and refined by full-matrix
least-squares analysis on F2 by using SHELXL. Hydrogen atoms were refined on the
riding model with isotropic thermal parameters set twenty percent greater than
those of their bonding partners. All other atoms were refined anisotropically.
19. X-ray crystallography of 6b: Orthorhombic, P212121 (no. 19), a = 8.389(2),
approximately 12 h, the solvent and excess POCl3 were evaporated on
a
rotary evaporator and finally on a vacuum pump for 2 h. The resultant residue
was redissolved in anhydrous MeOH (20 ml) and the solution was cooled to
ꢀ78 °C in a dry ice bath. To this solution was added NaBH4 (0.35 g, 9.2 mmol)
in five portions over 3 h. The reaction was quenched through the addition of
aqueous 10% HCl (10 ml), and the mixture was stirred at rt for 30 min. The
MeOH was evaporated on a rotary evaporator. The residue was basified by
adding 20% KOH at 0 °C. Water and CH2Cl2 were added in the latter stage to
solubilize the potassium salt and the amine. The mixture was extracted with
CH2Cl2 (4 ꢃ 20 ml), the combined organic layers were dried over MgSO4,
b = 9.881(3), c = 26.420(7), V = 2190.0(11) Å3, Z = 4,
q
calcd = 1.236 g cmꢀ3
rI), wR2 = 0.1194 (for all data). The
,
l
= 0.83 cmꢀ1, final R1 = 0.0486 (for I > 2
structure was solved by direct methods and refined by full-matrix least-
squares analysis on F2 by using SHELXL. Hydrogen atoms were refined on the
riding model with isotropic thermal parameters set twenty percent greater
than those of their bonding partners. All other atoms were refined
anisotropically. CCDC 751551 and CCDC 740136 contain the supplementary
crystallographic data. These can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.