Chlorotrimethylsilane activation of acylcyanamides for the synthesis of mono-N-acylguanidines

Article abstract of DOI:10.1021/jo201264j

A simple and efficient one-pot method for the synthesis of monoprotected guanidines is presented. Treatment of an acylcyanamide with chlorotrimethylsilane generates a reactive N-silylcarbodiimide capable of guanylating a variety of amines. Typically the reaction is complete in 15 min for primary and secondary aliphatic amines at rt. Hindered amines and anilines are also competent nucleophiles but require extended reaction times.

Full text of DOI:10.1021/jo201264j

NOTE
pubs.acs.org/joc
Chlorotrimethylsilane Activation of Acylcyanamides for the Synthesis
of Mono-N-acylguanidines
Ryan E. Looper,* Travis J. Haussener, and James B. C. Mack
Department of Chemistry, University of Utah, 315 South 1400 East, Salt lake City, Utah 84112, United States
S Supporting Information
b
ABSTRACT: A simple and efficient one-pot method for the syn-
thesis of monoprotected guanidines is presented. Treatment of
an acylcyanamide with chlorotrimethylsilane generates a reactive
N-silylcarbodiimide capable of guanylating a variety of amines.
Typically the reaction is complete in 15 min for primary and secondary
aliphatic amines at rt. Hindered amines and anilines are also competent nucleophiles but require extended reaction times.
he guanidinium ion represents an important molecular
architecture, valuable for its ability to engage receptors electro-
T
statically and through diverse hydrogen bond topologies.1 This has
made the guanidine a valuable synthetic target for applications as
varied as natural products chemistry,2 medicinal chemistry,3 su-
pramolecular chemistry,4 and asymmetric catalysis.5 As a result
there have been a large number of synthetic methods developed
to introduce the guanidine unit. Most of these methods rely on
the introduction of a diacylated guanidine unit to circumvent
problems associated with the reactivity or purification of this
basic functional group (Figure 1). In concert with a thiophilic
metal salt (typically Hg(II), Cu(I), or Ag(I)), the di-Boc-S-Me-
pseudothiourea (1) is by far the most commonly utilized reagent
to install the guanidine unit.6 The parent thiourea 2 can also be
used in conjunction with an activatingagent (typically Mukaiyama’s
reagent7 (3) or other suitable peptide coupling reagents8).
Goodman’s reagent9 (4) has also found wide utility since it is
capable of guanylating weakly nucleophilic amines. The pyrazole
transfer reagents 5 and 6 have also been developed to obviate the
use of toxic metals.10
Figure 1. Common guanylation reagents.
reported, but are unreactive or poorly reactive toward amines.10,11i
Alternatively, the differentially protected pyrazole 6 can be em-
ployed followed by selective removal of either the Boc or Cbz
group.15 These methods suffer from poor yields, require multiple
synthetic manipulations, or utilize costly reagents.
We were interested in a disconnection that relies on the
addition of an amine to an acylcyanamide. While it is known
that amines undergo addition to acylcyanamides, these reactions
typically require forcing conditions, are limited to anilines,16 and
are complicated by cyanamide decomposition thus limiting their
utility. Since acylcyanamides typically have pKa’s ∼ 2ꢀ4,17 this
renders them unreactive toward aliphatic amines via salt forma-
tion. We considered the possibility that treatment of the acylcya-
namide with a temporary activating agent might form a reactive
carbodiimide intermediate, lacking the acidic proton rendering it
capable of guanylating aliphatic or basic amines. Herein we report
our finding that silylation is particularly effective strategy to
activate acylcyanamides for nucleophilic addition.
We first began examining the direct activation of the cyan-
amide 718 and its reaction with benzylamine (Table 1). As
anticipated, there was no reaction in the absence of an activating
agent or in the presence of an exogenous base (entries 1 and 2).
Trifluoromethanesulfonic anhydride was capable of activat-
ing the cyanamide, however, these conditions led to complex
reaction mixtures and low yields of the guanidine 3 (entry 3).
These reagents are typically used to install the guanidine unit,
which after protecting group removal reveals a terminal mono- or
N,N-disubstituted guanidine. There have been a number of recent
reports however, aimed at developingchemistry to generate periph-
eral CꢀN bonds around the intact guanidine unit.11 These
methods target more highly substituted guanidinium ion struc-
tures but still incorporate the diacylated guanidine unit. We
became interested in the use of mono-N-acylguanidines in these
methodologies, anticipating the ability to exploit open nitrogen
valences for subsequent functionalization reactions.
The synthesis of mono-N-acylguanidines is typically accom-
plished by the acylation of guanidines with anhydrides or activated
acid derivatives. This method is frequently complicated by over
acylation due to the increased acidity of the initially formed
mono-N-acylguanidine.12 Alternatively they can be accessed by the
controlled hydrolysis of polyacyl or acyl-protected guanidines.13
Several methods have also been developed for their synthesis from
N-acyl-thioureas14 or N-acyl-pseudothioureas.14c The use of the
monoprotected versions of the pyrazole reagent 5 have also been
Received: June 20, 2011
Published: July 06, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Table 1. Survey of Activation Conditions
Table 2. Scope of the Guanylation Reaction
entry
activating agent
base
none
% yield
1
2
3
4
5
none
0
0
none
i-Pr2NEt
pyridine
pyridine
i-Pr2NEt
Tf2O
0
TMSCI
TMSCI
68
91
Scheme 1. Preparation of Benzyloxycarbonylcyanamide
Potassium Salt
The best results (entries 4 and 5) were obtained using chloro-
trimethylsilane as the activating agent.
We were excited by these initial experiments for several
reasons. (1) The reaction was very rapid, reaching completion in
just 15 min, (2) washing the crude reaction mixture with aqueous
acid and then base removed any unreacted amine or acylcyan-
amide respectively, delivering high purity material after workup,
and (3) the mono-Cbz guanidines are amenable to normal-phase
purification methods. One drawback, however, was the instability
of reagent 7 which in our hands would decompose significantly
after 2ꢀ3 days of storage at room temperature. It has previously
been observed that these acylcyanamides decompose to generate
a variety of diacyl- and cyanoguanidine byproducts.18 We anticipated
that the alkali salts of the cyanamide might provide a convenient,
shelf-stable version of this reagent. We developed an efficient
scalable preparation of the potassium salt of 7 (Scheme 1).19
Precipitation of the salt from methanol was found to be optimal
for producing 9 as a fine powder that could easily be manipulated.
Other recrystallization solvents or the sodium and lithium
counterions gave the corresponding salt as a fluffy solid or fine
plates which were difficult to handle or solubilize in subsequent
reaction conditions.
The potassium salt 9 has very poor solubility in THF, CH2Cl2,
toluene, and acetonitrile. However, treatment of a suspension
of the reagent in acetonitrile with TMSCl rapidly forms a milky
solution suggesting the formation of precipitated potassium chlo-
ride. After approximately 10 min, the original solid reagent 9
appeared to have been completely solubilized. To our delight,
addition of benzylamine to this mixture gave the guanidine 8a as
quickly and cleanly as our previous reaction conditions (Table 1,
entry 5), this time in 85% isolated yield after recrystallization
(Table 2, entry 1). Surveying the reactivity of this reagent showed
that it was quite general, reacting with other primary amines to
give the guanidines 8b,c in high yield after short reaction times
(entries 1ꢀ3). Secondary amines were also reactive, giving the
guanidines 8dꢀf in just 15 min (entries 4ꢀ6). Guanylation of a
hindered secondary amine, for example, diisopropylamine, was
also successful providing the guanidine 8g in 73% yield, but
required more time to reach completion (entry 7). Guanylation
of anilines required significantly longer reaction times (entries
8ꢀ11). Isolated yields of the guanidines 8hꢀk were well aligned
with the relative nucleophilicity of the parent aniline. While
electron deficient anilines can react (entry 11), the reagent is not
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The Journal of Organic Chemistry
NOTE
Scheme 2. Guanidine Deprotection
(50 mL) and washed with 10% Na2CO3 (50 mL), brine (50 mL) and the
organics driedover Na2SO4. Concentrationunder reducedpressure gavea
white solid which was recrystallized from toluene/ethyl acetate to give the
title compound as white microplates (337 mg, 85% yield). Rf = 0.07 (1:1)
1
hexanes/ethyl acetate. mp = 168ꢀ170 °C. H NMR (DMSO-d6, 500
MHz): δ 7.33ꢀ7.23 (m, 10H), 4.96 (s, 2H), 4.37 (br s, 2H). 13C NMR
(DMSO-d6, 125 MHz): δ 163.8, 162.1, 138.7, 129.6, 129.04, 128.9, 128.3,
128.1, 127.8, 127.6, 65.9, 44.1. IR (powder): 3472, 3282 (both m), 1640,
1616, 1588, 1558 (all s), 1424 (m), 1272, 1120 (both s). HRMS (ESI)
calculated for C16H18N3O2 m/z (M + H), 284.1399; obsd, 284.1402.
N-Benzyloxycarbonyl-N0-butylguanidine (8b). Prepared according
to the general procedure with purification on silica gel eluting with (1:1)
hexanes/ethyl acetate to give the title compound as a white solid (91%
yield). Rf = 0.15 (1:1) hexanes/ethyl acetate. mp = 73ꢀ75 °C. 1H NMR
(CDCl3, 500 MHz): δ 8.80ꢀ8.40 (br s, 1H), 7.35ꢀ7.24 (m, 5H),
7.00ꢀ6.40 (br s, 1H), 5.06 (s, 2H), 3.01 (t, J = 7.0 Hz, 2H), 1.47 (quint,
J = 7.0 Hz, 2H), 1.26 (sextet, J = 7.0 Hz, 2H), 0.86 (t, J = 7.0 Hz, 3H). 13C
NMR (CDCl3, 125 MHz): δ 163.9, 161.9, 137.7, 128.5, 127.8, 127.8,
66.1, 41.0, 31.1, 20.1, 13.8. IR (neat): 3407, 2957, 2931, 2872 (all w),
1622, 1582, 1278, 1103, 731 (all s). HRMS (ESI+) calculated for
C13H20N3O2 m/z (M + H), 250.1556; obsd, 250.1552.
capable of guanylating extremely electron poor substrates such as
p-nitroaniline under these conditions (entry 12).
Deprotection of these mono-Cbz protected guanidines can be
carried out under standard hydrogenolysis conditions to provide
the free guanidines or their HCl salts as exemplified by the
conversion of 8h to 10 (Scheme 2).
In summary, we have demonstrated that the activation of
acylcyanamides with chlorotrimethylsilane generates an efficient
reagent for the guanylation of aliphatic and aromatic amines. The
method is operationally simple, high yielding at room tempera-
ture, and adequate purification is usually achieved through
aqueous acid/base work up.
N-Benzyloxycarbonyl-N0-ethylindoleguanidine (8c). Prepared ac-
cording to the general procedure with purification on silica gel eluting
with 15% MeOH in CH2Cl2 to give the title compound as a white solid
(91% yield). Rf = 0.51 (15% MeOH in CH2Cl2). mp = 156ꢀ157.5 °C.
1H NMR (DMSO-d6, 500 MHz): δ 10.83 (br s, 1H), 7.57 (br s, 1H),
7.34ꢀ7.28 (m, 7H), 7.15 (br s, 2H), 7.07 (t, J=7.6 Hz, 1H), 6.95 (br s,
1H), 6.70 (br s, 1H), 4.97 (br s, 2H), 3.40 (br s, 2H), 2.86 (br s, 2H). 13C
NMR (DMSO-d6, 125 MHz, mixture of rotamers): δ 163.8, 162.1,
138.8, 136.9, 128.9, 128.3, 128.1, 123.4, 121.6, 119.1, 118.9, 112.3, 112.1,
66.0, 65.5, 42.0, 41.3, 26.1, 25.3. IR: 3407, 3313, 2941, 2361, 2339, 1617,
1119, 742.1. HRMS (ESI+) calculated for C19H20N4O2 m/z (M + H),
337.1665; obsd, 337.1665.
’ EXPERIMENTAL SECTION
Benzyloxycarbonylcyanamide (7). The title compound was
prepared according to Kwon with minor modifications.18 To a solution
of sodium hydroxide (46.9 g, 1.17 mol) in distilled water (750 mL) was
added cyanamide (49.6 g, 1.17 mol) in portions over 15 min. The
mixture was stirred for 30 min at which time dioxane (100 mL) was
added and the mixture cooled to 0 °C. Benzylchloroformate (95%
purity) (83.5 mL, 0.58 mol) was added dropwise via an additional funnel
over 1 h. The cooling bath was removed and the mixture stirred for 5 h at
room temperature. The mixture was then transferred to a separatory
funnel and washed with diethyl ether (3 ꢁ 100 mL). The aqueous phase
was acidified with concd HCl to pH = 2 and extracted with dichlo-
romethane (3 ꢁ 400 mL). The combined organics were then dried with
Na2SO4, filtered through a short plug of silica gel and concentrated to
give the cyanamide as a colorless oil that was used without further
purification (90.2 g, 92%). Physical data were identical with those
previously reported.
Benzyloxycarbonylcyanamide Potassium Salt (9). Potas-
siummetal(8.64 g, 0.221mol, 0.95equiv)wasaddedcarefullytomethanol
(300 mL) at 0 °C. After all of the metal was consumed the benzylox-
ycarbonylcyanamide (41.0 g, 0.232 mol) was added. After 10 min, a white
precipitate was formed. Toluene (300 mL) was added and the mixture
stirred at 0 °C for 30 min. The solids were collected on a B€uchner funnel,
rinsed with toluene (2 ꢁ 100 mL), hexanes (2 ꢁ 100 mL) and air-dried
to give the potassium salt as a white microscrystalline solid (34.7 g, 73%).
A second crop could be obtained from the mother liquor (3.21 g, 7%).
Rf = 0.28 (ethyl acetate). mp = 222ꢀ224 °C. 1H NMR (DMSO-d6, 500
MHz): δ 7.34ꢀ7.24 (m, 5H), 4.87 (s, 2H). 13C NMR (DMSO-d6, 125
MHz): δ 162.6, 138.7, 128.1, 127.3, 127.2, 122.1, 65.2. IR (powder):
3059, 3034 (both w), 2189 (s) 2144 (m), 1622 (s), 1394, 1338, 1306,
1177, 1145 (all m), 778, 758, 697 (all s). HRMS (ESIꢀ) calculated for
C9H7N2O2 [Mꢀ] m/z, 175.0508; obsd, 175.0511.
N-Benzyloxycarbonyl-N0-1,2,3,4-tetrahydroisoquinoline-guanidine
(8d). Prepared according to the general procedure and purified by
recrystallization from hexanes/acetone to give the title compound as
white plates (88% yield). Rf = 0.25 (1:1) hexanes/ethyl acetate. mp =
117ꢀ119 °C. 1H NMR (CDCl3, 500 MHz): δ 7.43 (d, J = 7.5 Hz, 2H),
7.33 (t, J = 7.5 Hz, 2H), 7.28ꢀ7.26 (m, 2H), 7.22ꢀ7.20 (m, 2H),
7.17ꢀ7.14 (m, 2H), 5.15 (s, 2H), 4.68 (s, 2H), 3.72 (br t, J = 5.0 Hz,
2H), 2.90 (t, J = 5.0 Hz, 2H). 13C NMR (DMSO-d6, 125 MHz): δ 163.9,
160.6, 137.6, 134.8, 132.7, 128.3, 128.0, 127.9, 127.7, 126.9, 126.6, 126.4,
66.6, 45.6, 41.6, 28.6. IR (neat): 3404, 3304, 3220 (all w), 1643 (m),
1583, 1537, 1438, 1295, 1240, 1216, 1091 (all s). HRMS (ESI)
calculated for C18H20N3O2 m/z (M + H), 310.1556; obsd, 310.1558.
N-Benzyloxycarbonyl-N0-morpholinoguanidine (8e). Prepared ac-
cording to the general procedure with purification on silica gel eluting
with 1:1 hexanes/ethyl acetate to give the title compound as a white
1
foam (92% yield). Rf = 0.21 (1:1) hexanes/ethyl acetate. H NMR
(CDCl3, 500 MHz): δ 7.37 (d, J = 7.5 Hz, 2H); 7.32 (t, J = 7.5 Hz, 2H);
7.26 (t, J = 7.5 Hz, 1H); 5.10 (s, 2H); 3.64 (t, J = 6.5, 4H); 3.48 (t, J = 6.5,
4H). 13C NMR (CDCl3, 125 MHz): δ 164.2, 160.9, 137.4, 66.9, 66.3,
44.0. IR (neat): 3397 (br), 2964, 2857, 1645, 1589, 1535, 1443, 1374,
1292, 1256, 1094 cmꢀ1. HRMS (ESI) calculated for C13H18N3O3 m/z
(M + H), 264.1348; obsd, 264.1349.
General Procedure for the Guanylation of Amines with 9. N-Benzy-
loxycarbonyl-N0-benzylguanidine (8a). Benzyloxycarbonylcyanamide
potassium salt (300 mg, 1.40 mmol) was slurried in acetonitrile (7.0 mL
to be 0.2 M). Chlorotrimethylsilane (194 μL, 1.50 mmol) was then added
and the mixture stirred for 10 min [or until all of thesolids have dissolved].
NOTE: The reaction mixture turns from a suspension to a milky white
consistency. Benzylamine (164 μL, 1.50 mmol) was then added. After 15
min, TLC analysis showed that the reaction was complete and the reaction
was concentrated under reduced pressure to approximately one-third of
the original volume. The mixture was then diluted with ethyl acetate
N-Benzyloxycarbonyl-N0-pyrrolidinoguanidine (8f). Prepared ac-
cording to the general procedure with purification on silica gel eluting
with 1:1 hexanes/ethyl acetate to give the title compound as a white solid
(90% yield). Rf = 0.16 (1:1) hexanes/ethyl acetate. mp = 147ꢀ149 °C.
1H NMR (CDCl3, 500 MHz): δ 7.39 (d, J = 7.5 Hz, 2H); 7.30 (t, J = 7.5
Hz, 2H); 7.24 (t, J = 7.5 Hz, 1H); 5.10 (s, 2H); 3.52 (br s, 2H); 3.26 (br
s, 2H); 1.91 (bs s, 4H). 13C NMR (CDCl3, 125 MHz): δ 164.0, 159.4,
137.9, 128.4, 128.2, 66.6, 47.2 (br), 25.3 (br). IR (neat): 3338, 3166,
2974, 2949, 2871, 1652, 1596, 1561, 1453, 1276, 1101 cmꢀ1. HRMS
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The Journal of Organic Chemistry
NOTE
(ESI) calculated for C13H18N3O2 m/z (M + H), 248.1399; obsd,
248.1401.
white powder (61 mg, 90%). Spectral data was identical to that
previously reported.20
N-Benzyloxycarbonyl ꢀN0, N0-diisopropylguanidine (8g). Prepared
according to the general procedure with recrystallization from hexanes/
acetone to give the title compound as a light yellow solid (73% yield).
’ ASSOCIATED CONTENT
1
S
Rf = 0.50 (1:1) hexanes/ethyl acetate. mp = 101ꢀ103 °C. H NMR
Supporting Information. General experimental details,
b
(CDCl3, 300 MHz): δ 7.40 (d, J = 7.5 Hz, 2H); 7.31 (t, J = 7.5 Hz, 2H);
7.25 (t, J = 7.5 Hz, 1H); 5.10 (s, 2H); 4.37 (br s, 2H); 1.23 (d, J = 7.2 Hz,
12H). 13C NMR (CDCl3, 125 MHz): δ 164.3, 160.6, 138.9, 128.4,
128.1, 127.6, 66.6, 45.4, 20.9. IR (neat): 3477, 3294 (both br), 3031,
2945, 1644, 1581, 1522, 1404, 1377, 1245, 1085 cmꢀ1. HRMS (ESI)
calculated for C15H24N3O2 m/z (M + H), 278.1869; obsd, 278.1869.
N-Benzyloxycarbonyl-N0-4-methoxyphenylguanidine (8h). Pre-
pared according to the general procedure with recrystallization from
toluene/ethyl acetate to give the title compound as a light purple solid
(83% yield). Rf = 0.10 (1:1) hexanes/ethyl acetate. mp = 172ꢀ173 °C.
1H NMR (CDCl3, 300 MHz): δ 7.3ꢀ7.2 (m, 5H), 7.13 (d, J = 8.7 Hz,
2H), 6.82 (d, J = 8.2 Hz, 2H), 4.98 (s, 2H), 3.79 (s, 3H). 13C NMR
(CDCl3, 75 MHz): δ 164.0, 161.6, 158.7, 137.5, 128.7, 128.4, 128.3,
127.8, 127.7, 115.0, 66.1, 55.6. IR (neat): 3475, 3272, 3067, 1640, 1606,
1574, 1391, 1276 cmꢀ1. HRMS (ESI) calculated for C16H18N3O3 m/z
(M + H), 300.1348; obsd, 300.1349.
1H, 13C spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: r.looper@utah.edu.
’ ACKNOWLEDGMENT
We are grateful to the National Institutes of Health, General
Medical Sciences (R01 GM 090082) for financial support of this
research.
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N- Benzyloxycarbonyl-N0-phenylguanidine (8i). Prepared accord-
ing to the general procedure with recrystallization from toluene/
ethyl acetate to give the title compound as a white solid (71% yield).
1
Rf = 0.15 (1:1) hexanes/ethyl acetate. mp = 167ꢀ170 °C. H NMR
(CDCl3, 500 MHz): δ 7.35ꢀ7.15 (m, 10H), 4.96 (s, 2H). 13C NMR
(CDCl3, 500 MHz): δ 163.8, 160.8, 137.4, 136.6, 129.9, 128.5, 127.9,
127.7, 127.1, 126.2, 66.2. IR: 3470, 3301, 3032, 2945, 1624, 1561, 1232,
1065, 697 cmꢀ1. HRMS (ESI) calculated for C15H16N3O2 m/z (M +
H), 270.1243; obsd, 270.1243.
N-Benzyloxycarbonyl-N0-methyl-N0-phenylguanidine (8j). Prepared
according to the general procedure with purification on silica gel eluting
with 1:1 hexanes/ethyl acetate to give the title compound as a colorless
oil (68% yield). Rf = 0.43 (1:1 hexanes/ethyl acetate). 1H NMR (CDCl3,
500 MHz): δ 7.48ꢀ7.42 (m, 4H); 7.38 (t, J = 7.5 Hz, 1H); 7.34 (t, J = 7.5
Hz, 2H); 7.29ꢀ7.25 (m, 3H); 5.16 (s, 3H); 3.39 (s, 3H). 13C NMR
(CDCl3, 125 MHz): δ 164.1, 160.7, 141.8, 137.6, 130.4, 128.4, 128.3,
128.1, 127.6, 127.4, 66.7, 38.6. IR (neat): 3477, 3294 (both br), 3031,
2945, 1644, 1581, 1522, 1404, 1377, 1245, 1085 cmꢀ1. HRMS (ESI)
calculated for C16H18N3O2 m/z (M + H), 284.1399; obsd, 284.1408.
N-Benzyloxycarbonyl-N0-3-fluorophenylguanidine (8k). Prepared
according to the general procedure with recrystallization from hexanes/
acetone to give the title compound as a light purple solid (63% yield). Rf
= 0.18 (1:1) hexanes/ethyl acetate. mp = 131ꢀ132 °C. 1H NMR
(CDCl3, 500 MHz): δ 7.29ꢀ7.23 (m, 6H), 6.97ꢀ6.90 (m, 3H), 5.00
(s, 2H). 13C NMR (CDCl3, 125 MHz): δ 163.5 (d, JCF = 249.5 Hz)
162.7 (br), 159.4 (br), 139.6 (br), 137.0, 131.0 (d, JCF = 9.1 Hz), 128.5,
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127.9, 121.2 (d, JCF = 3.0 Hz), 113.4 (d, JCF = 20.5 Hz), 113.0 (d, JCF
=
22.8 Hz), 66.4. IR (neat): 3473, 3305, 3065 (all w), 1627, 1595, 1563,
1263 (all s), 1145, 1078, 1063 (all m). HRMS (ESI) calculated for
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1-(4-Methoxyphenyl)guanidine (10). A 25 mL round-bottom
flask was charged with N-benzyloxycarbonyl-N0-4-methoxyphenylguani-
dine (8h) (100 mg, 0.33 mmol) and 10% palladium on charcoal (15 mg).
The flask was flushed with nitrogen and then MeOH (5 mL) and AcOH
(150 μL) was added. The mixture was stirred under a hydrogen atmo-
sphere for 2 h atwhich timeTLC showed the reactionto be complete. The
mixture was filtered through a plug of cotton and concentrated under
reduced pressure. The crude mixture was taken up in MeOH (2 mL) and
4 M HCl in diethyl ether (4 mL) was added. The mixture was again
concentrated and the resulting solid triturated with diethyl ether (3 ꢁ
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